Benzoimidazol-1,2-yl amides as Kv7 channel activators

ABSTRACT

Optionally substituted benzoimidazol-1,2-yl amides, such as compounds of Formula 1 or Formula 2, can be used to treat disorders associated with a Kv7 potassium channel activator. Compositions, medicaments, and dosage forms related to the treatment are also disclosed herein.

CROSS-REFERENCE TO RELATED CASES

The present application is a continuation of U.S. patent applicationSer. No. 16/460,449, filed Jul. 2, 2019, now U.S. Pat. No. 10,906,877,issued Feb. 2, 2021, which is a continuation of U.S. patent applicationSer. No. 15/879,792, filed Jan. 25, 2018, now U.S. Pat. No. 10,385,025,issued Aug. 20, 2019, which is a continuation of U.S. patent applicationSer. No. 15/339,590, filed Oct. 31, 2016, now U.S. Pat. No. 9,914,708,issued Mar. 13, 2018, which is a continuation of U.S. patent applicationSer. No. 14/853,815, filed Sep. 14, 2015, now U.S. Pat. No. 9,481,653,issued Nov. 1, 2016, which claims the benefit of U.S. Provisionalapplication No. 62/050,023, filed Sep. 12, 2014, the entire disclosuresof which are incorporated herein by reference. This application is alsois a continuation of U.S. patent application Ser. No. 16/346,292, filedApr. 30, 2019, which is a National Stage entry of InternationalApplication No. PCT/US2017/059393, filed Oct. 31, 2017, which is acontinuation-in-part of U.S. application Ser. No. 15/339,590, filed Oct.31, 2016, which, is now U.S. Pat. No. 9,914,708, issued Mar. 13, 2018,the entire disclosures of which are incorporated herein by reference.

This invention was made with government support under NS093160 awardedby the National Institutes of Health. The government has certain rightsin the invention.

BACKGROUND

Potassium (K⁺) channels, present on the plasma membranes of most celltypes, are the most diverse class of all ion channels and are associatedwith a wide range of physiological functions including the regulation ofthe electrical properties of excitable cells. The primary pore-forming(a) subunits of these highly selective cation channels are divided intothree primary structural classes based on the number of transmembrane(TM)-spanning regions and pore (P) regions: currently there are known tobe 6TM/1P, 2TM/1P and 4TM/2P K⁺ channels. The Kv7 genes (originallytermed KCNQ, a name assigned by the HUGO Gene Nomenclature Committee(HGNC)) were assigned to a subfamily of voltage-gated K⁺ channels by theInternational Union of Pharmacology (IUPHAR). The Kv7 subfamily consistsof five homologous pore-forming a subunits, Kv7.1-7.5, that have astructure typical of voltage-gated K⁺ channels with 6TM-spanning regions(S1-S6) flanked by intracellular N-terminal and C-terminal domains, atypical voltage-sensor domain located in S4 comprised of alternatingpositively-charged residues and a single P region between S5 and S6 ofeach subunit. The channels are formed as tetramers of the primary αsubunits, either as homotetramers or heterotetramers. Neurons are knownto express Kv7 channels comprised of Kv7.2-7.5 α subunits. Some of thesegene products may be exclusively neuronal while others, such as Kv7.4and Kv7.5, can be found in other tissues such as smooth and skeletalmuscle.

Native M-channels, and the corresponding macroscopic M-current, werefirst characterized in amphibian sympathetic neurons. M-channels werenotable because they were slowly activating and non-inactivating, activeat membrane potentials at or near the resting membrane potential ofneurons and muscarinic cholinergic agonists produced a reduction in theM-current, demonstrating a direct and inhibitory link between G-proteincoupled receptors (GPCRs) and a physiological K⁺ current. It was notuntil the cloning of this subfamily of genes that the pharmacologicaland biophysical identity was established between Kv7.2/7.3 (and likelyKv7.5/7.3) heteromultimers and the elusive ‘M’-channel, providingsignificant new evidence for their importance in neuronal regulation.

The distributions of these channels, both regionally anddevelopmentally, as well as their biophysical characteristics, supporttheir role in providing enduring resistance to depolarizing excitatoryinfluences. Under physiological conditions, as was demonstrated withnative M-channels, they can be very effective at regulating thesub-threshold excitability of certain neuronal populations withsignificant roles in regulating the frequency and ultimately the patternof action potential discharge in many types of neurons. Their importancein neuronal regulation was punctuated by the discovery that neuronal Kv7mutations lead to benign familial neonatal convulsions (BFNC) indicatingthat reduction or removal of the influence of Kv7.2 and Kv7.3 channelscan dramatically alter neuronal excitability. Mutation analysesdemonstrated their involvement in BFNC and suggested their utility astargets for anti-epileptic drugs (AEDs).

Unlike established pharmacological terminology for GPCRs, the mode ofaction of K⁺ channel modulators, in particular compounds that activatethe channel, is still being refined. The application of voltage-clamptechniques to the study of ion channel pharmacology enabled detailedbiophysical studies on either whole-cell currents or single channels,allowing some characterization of the nature of compound-channelinteractions but not preventing ongoing confusion around theterminology. The term opener or activator is commonly used throughoutthe literature but does not adequately describe the mode of action ofall these ‘positive modulator’ compounds. In general, openers oractivators are expected to increase the open probability of the channelor increase macroscopic current amplitude, but this nomenclature isreally too simplistic. For example, retigabine, the first publiclydisclosed Kv7 opener, has a complex and interesting profile in that ithas inhibitory activity at higher membrane potentials. Neuronal Kv7channel openers may work in concert with the activity of a channel overthe ‘normal’ activation-voltage range and enhance currents withoutsignificantly affecting the activation threshold while others cansignificantly alter the activation threshold. In addition, some openersappear to remove the voltage-dependence of activation entirely. Whetherthese effects represent some continuum is currently unclear since theeffects are often concentration-dependent. Clearly, the modes ofinteraction of compounds that can increase channel current are complexand in most cases not well understood and the implications of theseprofiles on neuronal responsiveness and systems physiology are alsounclear. Retigabine is modestly potent, not highly specific, but it is avery effective opener of Kv7.2, Kv7.5 and heteromultimeric Kv7 channels.Its effects are characterized by a significant increase in channelcurrent over a narrow voltage range. As mentioned above, at morepositive voltages the opener is less effective and under some conditionschannel current significantly decreases at more positive voltagesrelative to control currents (this ‘crossover’ voltage-dependence ofopener action is a characteristic of many neuronal Kv7 channel openers).This effect is also concentration-dependent and is more pronounced athigher concentrations.

SUMMARY

Described herein are compounds that can be potent and/or at least biasedfor the Kv7.2/7.3 heteromultimer over the Kv7.4 homomultimer. Thesecompounds may have reduced untoward side effects as compared toretigabine.

Some embodiments include a compound represented by Formula 1:

wherein D is optionally substituted C₃₋₆ carbocyclyl, C₂₋₅ heterocyclyl,or C₁₋₄ alkyl; Bz is optionally substituted benzoimidazol-1,2-diyl oroptionally substituted benzoimidazol-1,2,6-triyl; A is C₁₋₈ alkyl; X isH, F, CF₃, optionally substituted phenyl, or optionally substitutedpyridinyl; and Y is H, F, Cl, Br, I, or a moiety having a molecularweight of 15 Da to 300 Da and consisting of 2 to 5 chemical elements,wherein the chemical elements are independently C, H, O, N, S, F, Cl, orBr.

Some embodiments include a composition comprising a compound describedherein, such as a compound of Formula 1 or Formula 2, wherein thecomposition is pharmaceutically acceptable.

Some embodiments include a pharmaceutical dosage form comprising acompound described herein, such as a compound of Formula 1 or Formula 2.

Some embodiments include a method of treating a disorder associated witha Kv7 potassium channel activator comprising administering an effectiveamount of a compound described herein, such as a compound of Formula 1or Formula 2, to a mammal in need thereof.

Some embodiments include use of a compound of Formula 1 or Formula 2, inthe manufacture of a medicament for the treatment of a disorderassociated with a Kv7 potassium channel activator.

DETAILED DESCRIPTION

Unless otherwise indicated, when a compound or chemical structuralfeature such as benzoimidazol-1,2-yl is referred to as being “optionallysubstituted,” it includes a feature that has no substituents (i.e.unsubstituted), or a feature that is “substituted,” meaning that thefeature has one or more substituents. The term “substituent” has thebroadest meaning known to one of ordinary skill in the art and includesa moiety that replaces one or more hydrogen atoms attached to a parentcompound or structural feature. In some embodiments, a substituent maybe an ordinary organic moiety known in the art, which may have amolecular weight (e.g. the sum of the atomic masses of the atoms of thesubstituent) of 15 Da to 50 Da, 15 Da to 100 Da, 15 Da to 150 Da, 15 Dato 200 Da, 15 Da to 300 Da, or 15 Da to 500 Da. In some embodiments, asubstituent comprises, or consists of: 0-30, 0-20, 0-10, or 0-5 carbonatoms; and 0-30, 0-20, 0-10, or 0-5 heteroatoms, wherein each heteroatommay independently be: N, O, S, Si, F, Cl, Br, or I; provided that thesubstituent includes one C, N, O, S, Si, F, Cl, Br, or I atom. Examplesof substituents include, but are not limited to, alkyl, alkenyl,alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl,hydroxy, alkoxy, aryloxy, acyl, acyloxy, alkylcarboxylate, thiol,alkylthio, cyano, halo, thiocarbonyl, O-carbamyl, N-carbamyl,O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido,N-sulfonamido, isocyanato, thiocyanato, isothiocyanato, nitro, silyl,sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxyl,trihalomethanesulfonyl, trihalomethanesulfonamido, amino, etc.

For convenience, the term “molecular weight” is used with respect to amoiety or part of a molecule to indicate the sum of the atomic masses ofthe atoms in the moiety or part of a molecule, even though it may not bea complete molecule.

The structures associated with some of the chemical names referred toherein are depicted below. These structures may be unsubstituted, asshown below, or a substituent may independently be in any positionnormally occupied by a hydrogen atom when the structure isunsubstituted. Unless a point of attachment is indicated by

attachment may occur at any position normally occupied by a hydrogenatom.

As used herein, the term “alkyl” has the broadest meaning generallyunderstood in the art and may include a moiety composed of carbon andhydrogen containing no double or triple bonds. Alkyl may be linearalkyl, branched alkyl, cycloalkyl, or a combination thereof and in someembodiments, may contain from one to thirty-five carbon atoms. In someembodiments, alkyl may include C₁₋₁₀ linear alkyl, such as methyl(—CH₃), methylene (—CH₂—), ethyl (—CH₂CH₃), ethylene (—C₂H₄—), propylene(—C₃CH₆—), n-butyl (—CH₂CH₂CH₂CH₃), n-pentyl (—CH₂CH₂CH₂CH₂CH₃), n-hexyl(—CH₂CH₂CH₂CH₂CH₂CH₃), etc.; C₃₋₁₀ branched alkyl, such as C₃H₇ (e.g.isopropyl), C₄H₉ (e.g. branched butyl isomers), C₅H₁₁ (e.g. branchedpentyl isomers), C₆H₁₃ (e.g. branched hexyl isomers), C₇H₁₅ (e.g. heptylisomers), etc.; C₃₋₁₀ cycloalkyl, such as C₃H₅ (e.g. cyclopropyl), C₄H₇(e.g. cyclobutyl isomers such as cyclobutyl, methylcyclopropyl, etc.),C₅H₉ (e.g. cyclopentyl isomers such as cyclopentyl, methylcyclobutyl,dimethylcyclopropyl, etc.) C₆H₁₁ (e.g. cyclohexyl isomers), C₇H₁₃ (e.g.cycloheptyl isomers), etc.; and the like.

As used herein, the term “carbocyclyl” has the broadest meaninggenerally understood in the art and includes rings free of heteroatoms,such as cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, etc.; cycloalkenyl, e.g. cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclohexenyl; cycloalkynyl, e.g. cyclopropynyl,cyclobutynyl, cyclopentynyl, cyclohexynyl; as well as aryl rings free ofheteroatoms.

As used herein the term “aryl” has the broadest meaning generallyunderstood in the art and may include an aromatic ring or aromatic ringsystem such as phenyl, naphthyl, etc.

The term “heterocyclyl” includes any ring or ring system containing aheteroatom such as N, O, S, P, etc. Heterocyclyl includes heteroarylrings or ring systems (such as those listed below) and non-aromaticrings or ring systems. Examples of non-aromatic heterocyclyl includeazetidinyl, oxatanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl,thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl,thiazolidinyl, isothiazolidinyl, dioxalanyl, dithiolanyl,tetrahydropyranyl, piperidinyl, piperazinyl, morpholino, etc.

The term “heteroaryl” also has the meaning understood by a person ofordinary skill in the art and includes an “aryl” which has one or moreheteroatoms in the ring or ring system, such as pyridinyl, furyl,thienyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, oxadiazolyl,isoxazolyl, indolyl, quinolinyl, benzofuranyl, benzothienyl,benzooxazolyl, benzothiazolyl, benzoimidazolyl, etc.

Unless otherwise indicated, any reference to a compound herein bystructure, name, or any other means includes pharmaceutically acceptablesalts, such as HCl, HBr, HI, H₂SO₄, acetate, citrate, sodium, potassium,and ammonium salts; prodrugs, such as ester prodrugs; alternate solidforms, such as polymorphs, solvates, hydrates, etc.; tautomers; or anyother chemical species that may rapidly convert to a compound describedherein under conditions in which the compounds are used as described.

If stereochemistry is not indicated, a name or structural representationincludes any stereoisomer or any mixture of stereoisomers.

With respect to Formula 1, Bz can be optionally substitutedbenzoimidazol-1,2-yl. If the benzoimidazol-1,2-yl is substituted, it mayhave 1, 2, 3, or 4 substituents. Any substituent may be included on thebenzoimidazol-1,2-yl. In some embodiments, some or all of thesubstituents on the benzoimidazol-1,2-yl may have: from 0 to 10 carbonatoms and from 0 to 10 heteroatoms, wherein each heteroatom isindependently: O, N, S, F, Cl, Br, or I (provided that there is at least1 non-hydrogen atom); and/or a molecular weight of 15 g/mol to 500g/mol. In some embodiments, some or all of the substituents may eachhave a molecular weight of 15 Da to 200 Da, 15 Da to 100 Da, or 15 Da to50 Da, and consist of 2 to 5 chemical elements, wherein the chemicalelements are independently C, H, O, N, S, F, Cl, or Br. In someembodiments, Bz can be optionally substituted benzoimidazol-1,2-diyl. Insome embodiments, Bz can be optionally substituted benzoimidazol-1, 2,6-triyl.

For example, with respect to Formula 1, the substituents of Bz may beC₁₋₁₀ optionally substituted alkyl, such as CH₃, C₂H₅, C₃H₇, cyclicC₃H₅, C₄H₉, cyclic C₄H₇, C₅H₁₁, cyclic C₅H₉, C₆H₁₃, cyclic C₆H₁₁, etc.,which may be optionally substituted; C₁₋₁₀ optionally substituted alkoxysuch as OCH₃, OC₂H₅, OC₃H₇, cyclic OC₃H₅, OC₄H₉, cyclic OC₄H₇, OC₅H₁₁,cyclic OC₅H₉, OC₆H₁₃, cyclic OC₆H₁₁, etc.; halo, such as F, Cl, Br, I;OH; CN; NO₂; C₁₋₆ fluoroalkyl, such as CF₃, CF₂H, C₂F₅, etc.; C₁₋₆fluoroalkoxy, such as OCF₃, OCF₂H, OC₂F₅, etc.; a C₁₋₁₀ ester such as—O₂CCH₃, —CO₂CH₃, —O₂CC₂H₅, —CO₂C₂H₅, —O₂C-phenyl, —CO₂-phenyl, etc.; aC₁₋₁₀ ketone such as —COCH₃, —COC₂H₅, —COC₃H₇, —CO-phenyl, etc.; or aC₁₋₁₀ amine such as NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)C₂H₅, etc. In someembodiments, a substituent of Bz may be F, Cl, Br, I, CN, NO₂, C₁₋₄alkyl, C₁₋₄ alkyl-OH, C₁₋₃ O-alkyl, CF₃, COH, C₁₋₄ CO-alkyl, CO₂H, C₁₋₄CO₂-alkyl, NH₂, or C₁₋₄ alkylamino.

Some embodiments include a compound represented by Formula 2:

With respect to any relevant structural representation, such as Formula1 or 2, D is optionally substituted C₃₋₆ carbocyclyl or C₂₋₅heterocyclyl. If D is substituted cyclobutyl, it may have 1, 2, 3, 4, 5,6, or 7 substituents. If D is substituted phenyl, it may have 1, 2, 3,4, or 5 substituents. If D is substituted isoxazolyl, it may have 1 or2. D may include any substituent. In some embodiments, some or all ofthe substituents of D may have: from 0 to 10 carbon atoms and from 0 to10 heteroatoms, wherein each heteroatom is independently: O, N, S, F,Cl, Br, or I (provided that there is at least 1 non-hydrogen atom);and/or a molecular weight of 15 g/mol to 500 g/mol. In some embodiments,some or all of the substituents may each have a molecular weight of 15Da to 200 Da, 15 Da to 100 Da, or 15 Da to 50 Da, and consist of 2 to 5chemical elements, wherein the chemical elements are independently C, H,O, N, S, F, Cl, or Br.

For example, with respect to any relevant structural representation,such as Formula 1 or 2, the substituents of D may be C₁₋₁₀ optionallysubstituted alkyl, such as CH₃, C₂H₅, C₃H₇, cyclic C₃H₅, C₄H₉, cyclicC₄H₇, C₅H₁₁, cyclic C₅H₉, C₆H₁₃, cyclic C₆H₁₁, etc., which may beoptionally substituted; C₁₋₁₀ optionally substituted alkoxy such asOCH₃, OC₂H₅, OC₃H₇, cyclic OC₃H₅, OC₄H₉, cyclic OC₄H₇, OC₅H₁₁, cyclicOC₅H₉, OC₆H₁₃, cyclic OC₆H₁₁, etc.; halo, such as F, Cl, Br, I; OH; CN;NO₂; C₁₋₆ fluoroalkyl, such as CF₃, CF₂H, C₂F₅, etc.; C₁₋₆ fluoroalkoxy,such as OCF₃, OCF₂H, OC₂F₅, etc.; a C₁₋₁₀ ester such as —O₂CCH₃,—CO₂CH₃, —O₂CC₂H₅, —CO₂C₂H₅, —O₂C-phenyl, —CO₂-phenyl, etc.; a C₁₋₁₀ketone such as —COCH₃, —COC₂H₅, —COC₃H₇, —CO-phenyl, etc.; or a C₁₋₁₀amine such as NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)C₂H₅, etc. In someembodiments, a substituent of D may be F, Cl, Br, I, CN, NO₂, C₁₋₄alkyl, C₁₋₄ alkyl-OH, C₁₋₃ O-alkyl, CF₃, COH, C₁₋₄ CO-alkyl, CO₂H, C₁₋₄CO₂-alkyl, NH₂, or C₁₋₄ alkylamino.

With respect to any relevant structural representation, such as Formula1 or 2, in some embodiments, D is:

or optionally substituted C₂₋₄ alkyl.

With respect to any relevant structural representation, such as Formula1 or 2, in some embodiments, D is optionally substituted cyclobutyl,optionally substituted phenyl, optionally substituted isoxazolyl, orisopropyl.

With respect to any relevant structural representation, such as Formula1 or 2, in some embodiments, D is optionally substituted cyclobutyl. Insome embodiments, D is cyclobutyl. In some embodiments, D is

With respect to any relevant structural representation, such as Formula1 or 2, in some embodiments, D is isopropyl.

With respect to any relevant structural representation, such as Formula1 or 2, in some embodiments, D is t-butyl, or tert-butyl.

With respect to any relevant structural representation, such as Formula1 or 2, in some embodiments, D is optionally substituted phenyl. In someembodiments D is

With respect to any relevant structural representation, such as Formula1 or 2, in some embodiments, D is optionally substituted pyridinyl, suchas optionally substituted pyridiny-2-yl, pyridin-3-yl, or pyridin-4-yl.In some embodiments, D is

With respect to any relevant structural representation, such as Formula1 or 2, in some embodiments, D is optionally substituted isoxazolyl. Insome embodiments, D is

With respect to any relevant structural representation, such as Formula1 or 2, A is C₂₋₈ alkyl, such as linear or branched

linear or branched

linear or branched

linear or branched

linear or branched

containing one ring,

containing one ring,

containing one ring,

containing one ring, or

containing a bicyclic ring system.

With respect to any relevant structural representation, such as Formula1 or 2, X is H, F, CF₃, optionally substituted phenyl, or optionallysubstituted pyridinyl. In some embodiments, X is H. In some embodiments,X is F. In some embodiments, X is CF₃.

With respect to any relevant structural representation, such as Formula1 or 2, if X is substituted phenyl, it may have 1, 2, 3, 4, or 5,substituents. If X is substituted pyridinyl, it may have 1, 2, 3, or 4substituents. In some embodiments, some or all of the substituents of Xmay have: from 0 to 10 carbon atoms and from 0 to 10 heteroatoms,wherein each heteroatom is independently: O, N, S, F, Cl, Br, or I(provided that there is at least 1 non-hydrogen atom); and/or amolecular weight of 15 g/mol to 500 g/mol. In some embodiments, some orall of the substituents may each have a molecular weight of 15 Da to 200Da, 15 Da to 100 Da, or 15 Da to 50 Da, and consist of 2 to 5 chemicalelements, wherein the chemical elements are independently C, H, O, N, S,F, Cl, or Br.

For example, with respect to any relevant structural representation,such as Formula 1 or 2, the substituents of X may be C₁₋₁₀ optionallysubstituted alkyl, such as CH₃, C₂H₅, C₃H₇, cyclic C₃H₅, C₄H₉, cyclicC₄H₇, C₅H₁₁, cyclic C₅H₉, C₆H₁₃, cyclic C₆H₁₁, etc., which may beoptionally substituted; C₁₋₁₀ optionally substituted alkoxy such asOCH₃, OC₂H₅, OC₃H₇, cyclic OC₃H₅, OC₄H₉, cyclic OC₄H₇, OC₅H₁₁, cyclicOC₅H₉, OC₆H₁₃, cyclic OC₆H₁₁, etc.; halo, such as F, Cl, Br, I; OH; CN;NO₂; C₁₋₆ fluoroalkyl, such as CF₃, CF₂H, C₂F₅, etc.; C₁₋₆ fluoroalkoxy,such as OCF₃, OCF₂H, OC₂F₅, etc.; a C₁₋₁₀ ester such as —O₂CCH₃,—CO₂CH₃, —O₂CC₂H₅, —CO₂C₂H₅, —O₂C-phenyl, —CO₂-phenyl, etc.; a C₁₋₁₀ketone such as —COCH₃, —COC₂H₅, —COC₃H₇, —CO-phenyl, etc.; or a C₁₋₁₀amine such as NH₂, NH(CH₃), N(CH₃)₂, N(CH₃)C₂H₅, etc. In someembodiments, a substituent of X may be F, Cl, Br, I, CN, NO₂, C₁₋₄alkyl, C₁₋₄ alkyl-OH, C₁₋₃ O-alkyl, CF₃, COH, C₁₋₄ CO-alkyl, CO₂H, C₁₋₄CO₂-alkyl, NH₂, or C₁₋₄ alkylamino.

With respect to any relevant structural representation, such as Formula1 or 2, Y is H, F, Cl, Br, I, or a moiety having a molecular weight of15 Da to 300 Da and consisting of 2 to 5 chemical elements, wherein thechemical elements are independently C, H, O, N, S, F, Cl, or Br. In someembodiments, Y is H, F, Cl, Br, I, CN, —COH, C₁₋₆—CO-alkyl, CF₃, OH,C₁₋₅ O-alkyl, C₀₋₆ amino, or C₀₋₆ fluoroamino. In some embodiments, Y isH, F, CF₃, OH, C₁₋₅ O-alkyl, C₀₋₆ amino, or C₀₋₆ fluoroamino. In someembodiments, Y is H. In some embodiments, Y is OH. In some embodiments,Y is F. In some embodiments, Y is CF₃. In some embodiments, Y is C₁₋₃O-alkyl, such as —OCH₃, OC₂H₅, OC₃H₇, etc. In some embodiments, Y isC₀₋₆ fluoroamino. In some embodiments, Y is optionally substitutedtetrahydropyranyl, such as

In some embodiments Y may include a C₁₋₈ alkyl that may include one ortwo C₃₋₆ carbocyclyl rings. In some embodiments, wherein Y includes atleast one carbocyclyl rings, the rings may be connected to each other.In some embodiments, Y is —C(CF₃)₂OH (or1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl). In some embodiments Y is

(or methyl(2,2,2-trifluoroethyl)amino). In some embodiments, Y isdimethylamino.

With respect to any relevant structural representation, such as Formula1 or 2, in some embodiments

is C₂₋₈ alkyl, such as

With respect to any relevant structural representation, such as Formula1 or 2, in some embodiments

is C₂₋₈ hydroxyalkyl, such as

With respect to any relevant structural representation, such as Formula1 or 2, in some embodiments

is C₂₋₈ fluoroalkyl such as

With respect to any relevant structural representation, such as Formula1 or 2, in some embodiments

is C₂₋₈ alkoxyalkyl, such as

With respect to any relevant structural representation, such as Formula1 or 2, in some embodiments

is C₂₋₈ hydroxyfluoroalkyl, such as

With respect to any relevant structural representation, such as Formula1 or 2, in some embodiments

is optionally substituted 2-hydroxy-2-phenylethyl, such as

With respect to any relevant structural representation, such as Formula1 or 2, in some embodiments

is optionally substituted 2-hydroxy-2-phenylpyridinyl, such as

With respect to any relevant structural representation, such as Formula1 or 2, in some embodiments

is optionally substituted C₂₋₈ fluoroaminoalkyl, such as

Generally R¹⁻¹⁸, may be H or any substituent, such as a substituenthaving 0 to 12 atoms or 0 to 6 carbon atoms and 0 to 5 heteroatoms,wherein each heteroatom is independently: O, N, S, F, Cl, Br, or I,and/or having a molecular weight of 15 g/mol to 300 g/mol. Any of R¹⁻¹⁸may comprise: a) 1 or more alkyl moieties optionally substituted with,or optionally connected by or to, b) 1 or more functional groups, suchas C═C, C≡C, CO, CO₂, CON, NCO₂, OH, SH, O, S, N, N═C, F, Cl, Br, I, CN,NO₂, CO₂H, NH₂, etc.; or may be a substituent having no alkyl portion,such as F, Cl, Br, I, NO₂, CN, NH₂, OH, COH, CO₂H, etc. In someembodiments, each of R¹⁻¹⁸ is independently H, F, Cl, Br, I, or asubstituent having a molecular weight of 15 Da to 300 Da, 15 Da to 200Da, 15 Da to 100 Da, or 15 Da to 60 Da, and consisting of 2 to 5chemical elements, wherein the chemical elements are independently C, H,O, N, S, F, Cl, or Br.

With respect to any relevant structural representation, such as Formula2, some non-limiting examples of R¹⁻¹⁸ may include R^(A), F, Cl, Br, CN,OR^(A), C₁₋₃ fluoroalkyl, C₁₋₄ hydroxyalkyl, NO₂, NR^(A)R^(B), COR^(A),CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments,R¹⁻¹⁸ may be H; F; Br; CN; C₁₋₃ fluoroalkyl, such as CHF₂, CF₃, etc; OH;NH₂; C₁₋₆ alkyl, such as methyl, ethyl, propyl isomers (e.g. n-propyland isopropyl), cyclopropyl, butyl isomers, cyclobutyl isomers (e.g.cyclobutyl and methylcyclopropyl), pentyl isomers, cyclopentyl isomers,hexyl isomers, cyclohexyl isomers, etc.; C₁₋₆ alkoxy, such as —O-methyl,—O-ethyl, isomers of —O-propyl, —O cyclopropyl, isomers of —O-butyl,isomers of —O-cyclobutyl, isomers of —O-pentyl, isomers of—O-cyclopentyl, isomers of —O-hexyl, isomers of —O-cyclohexyl, etc.;C₁₋₄ hydroxyalkyl, such as —CH₂OH, —C₂H₄—OH, —C₃H₆—OH, C₄H₈—OH, etc.;C₂₋₅—CO₂-alkyl, such as —CO₂—CH₃, —CO₂—C₂H₅, —CO₂—C₃H₇, —CO₂—C₄H₉, etc.

With respect to any relevant structural representation, each R^(A) mayindependently be H, or C₁₋₁₂ alkyl, including: linear or branched alkylhaving a formula C_(a)H_(a+1), or cycloalkyl having a formulaC_(a)H_(a−1), wherein a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12,such as linear or branched alkyl of a formula: CH₃, C₂H₅, C₃H₇, C₄H₉,C₅H₁₁, C₆H₁₃, C₇H₁₅, C₈H₁₇, C₉H₁₉, C₁₀H₂₁, etc., or cycloalkyl of aformula: C₃H₅, C₄H₇, C₅H₉, C₆H₁₁, C₇H₁₃, C₈H₁₅, C₉H₁₇, C₁₀H₁₉, etc. Insome embodiments, R^(A) may be H or C₁₋₆ alkyl. In some embodiments,R^(A) may be H or C₁₋₃ alkyl. In some embodiments, R^(A) may be H orCH₃. In some embodiments, R^(A) may be H.

With respect to any relevant structural representation, each R^(B) mayindependently be H, or C₁₋₁₂ alkyl, including: linear or branched alkylhaving a formula C_(a)H_(a+1), or cycloalkyl having a formulaC_(a)H_(a−1), wherein a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12,such as linear or branched alkyl of a formula: CH₃, C₂H₅, C₃H₇, C₄H₉,C₅H₁₁, C₆H₁₃, C₇H₁₅, C₈H₁₇, C₉H₁₉, C₁₀H₂₁, etc., or cycloalkyl of aformula: C₃H₅, C₄H₇, C₅H₉, C₆H₁₁, C₇H₁₃, C₈H₁₅, C₉H₁₇, C₁₀H₁₉, etc. Insome embodiments, R^(B) may be H or C₁₋₃ alkyl. In some embodiments,R^(B) may be H or CH₃. In some embodiments, R^(B) may be H.

With respect to any relevant structural representation, such as Formula2, in some embodiments R¹ is H, F, Cl, Br, CN, OCH₃, CHF₂, CF₃,C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₄ hydroxyalkyl. In some embodiments,R¹ is H, Cl, Br, CN, OCH₃, CHF₂, CF₃, —CO₂CH₂CH₃, —CH₂OH,

In some embodiments, R¹ is H. In some embodiments, R¹ is Cl. In someembodiments, R¹ is Br. In some embodiments, R¹ is CN. In someembodiments, R¹ is OCH₃. In some embodiments, R¹ is CHF₂. In someembodiments, R¹ is CF₃. In some embodiments, R¹ is —CO₂CH₂CH₃. In someembodiments, R¹ is —CH₂OH. In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is —OCH₃, —CN, —CF₃, —CH₂OH, —COOCH₂CH₃,—C(CH₃)₂OH, —CHOHCH₂CH₃, —CHOHCH₃, —CHF₂, —CH(CH₃)₂, —C(CH₂CH₃)OH,—CH₂CO OCH₂CH₃, —CH₂C(CH₃)₂OH, —CH₂COOH, or —CH₂CON(CH₃)₂.

With respect to the embodiments recited in this paragraph, in someembodiments, the remaining groups of R¹⁻¹⁸ may independently be R^(A),F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₄ hydroxyalkyl, NO₂,NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B),etc. In some embodiments, the remaining groups of R¹⁻¹⁸ may be H, F, Cl,Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation, such as Formula2, in some embodiments R² is H, F, Cl, Br, CN, OCH₃, CHF₂, CF₃,C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₄ hydroxyalkyl. In some embodiments,R² is H. In some embodiments, R² is CH₂OH. In some embodiments, R² is—CO₂CH₃. With respect to the embodiments recited in this paragraph, insome embodiments, the remaining groups of R¹⁻¹⁸ may independently beR^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₄ hydroxyalkyl, NO₂,NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B),etc. In some embodiments, the remaining groups of R¹⁻¹⁸ may be H, F, Cl,Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl. In some embodiments, R² is —CH₂OH,—CO₂Me, or —C(CH₃)₂OH.

With respect to any relevant structural representation, such as Formula2, in some embodiments R³ is H, F, Cl, Br, CN, OCH₃, CHF₂, CF₃,C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₄ hydroxyalkyl. In some embodiments,R³ is H. With respect to the embodiments recited in this paragraph, insome embodiments, the remaining groups of R¹⁻¹⁸ may independently beR^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₄ hydroxyalkyl, NO₂,NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B),etc. In some embodiments, the remaining groups of R¹⁻¹⁸ may be H, F, Cl,Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation, such as Formula2, in some embodiments R⁴ is H, F, Cl, Br, CN, OCH₃, CHF₂, CF₃,C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₄ hydroxyalkyl. In some embodiments,R⁴ is H. In some embodiments, R⁴ is CH₃. In some embodiments, R⁴ is CF₃.With respect to the embodiments recited in this paragraph, in someembodiments, the remaining groups of R¹⁻¹⁸ may independently be R^(A),F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₄ hydroxyalkyl, NO₂,NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B),etc. In some embodiments, the remaining groups of R¹⁻¹⁸ may be H, F, Cl,Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation, such as Formula2, in some embodiments R⁵ is H, F, Cl, Br, CN, OCH₃, CHF₂, CF₃,C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₄ hydroxyalkyl. In some embodiments,R⁵ is H. With respect to the embodiments recited in this paragraph, insome embodiments, the remaining groups of R¹⁻¹⁸ may independently beR^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₄ hydroxyalkyl, NO₂,NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B),etc. In some embodiments, the remaining groups of R¹⁻¹⁸ may be H, F, Cl,Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation, such as Formula2, in some embodiments R⁶ is H, F, Cl, Br, CN, OCH₃, CHF₂, CF₃,C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₄ hydroxyalkyl. In some embodiments,R⁶ is H. With respect to the embodiments recited in this paragraph, insome embodiments, the remaining groups of R¹⁻¹⁸ may independently beR^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₄ hydroxyalkyl, NO₂,NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B),etc. In some embodiments, the remaining groups of R¹⁻¹⁸ may be H, F, Cl,Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation, such as Formula2, in some embodiments R⁷ is H, F, Cl, Br, CN, OCH₃, CHF₂, CF₃,C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₄ hydroxyalkyl. In some embodiments,R⁷ is H. With respect to the embodiments recited in this paragraph, insome embodiments, the remaining groups of R¹⁻¹⁸ may independently beR^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₄ hydroxyalkyl, NO₂,NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B),etc. In some embodiments, the remaining groups of R¹⁻¹⁸ may be H, F, Cl,Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation, such as Formula2, in some embodiments R⁸ is H, F, Cl, Br, CN, OCH₃, CHF₂, CF₃,C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₄ hydroxyalkyl. In some embodiments,R⁸ is H. With respect to the embodiments recited in this paragraph, insome embodiments, the remaining groups of R¹⁻¹⁸ may independently beR^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₄ hydroxyalkyl, NO₂,NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B),etc. In some embodiments, the remaining groups of R¹⁻¹⁸ may be H, F, Cl,Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation, such as Formula2, in some embodiments R⁹ is H, F, Cl, Br, CN, OCH₃, CHF₂, CF₃,C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₄ hydroxyalkyl. In some embodiments,R⁹ is H. With respect to the embodiments recited in this paragraph, insome embodiments, the remaining groups of R¹⁻¹⁸ may independently beR^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₄ hydroxyalkyl, NO₂,NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B),etc. In some embodiments, the remaining groups of R¹⁻¹⁸ may be H, F, Cl,Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation, such as Formula2, in some embodiments R¹⁰ is H, F, Cl, Br, CN, OCH₃, CHF₂, CF₃,C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₄ hydroxyalkyl. In some embodiments,R¹⁰ is H. With respect to the embodiments recited in this paragraph, insome embodiments, the remaining groups of R¹⁻¹⁸ may independently beR^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₄ hydroxyalkyl, NO₂,NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B),etc. In some embodiments, the remaining groups of R¹⁻¹⁸ may be H, F, Cl,Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation, such as Formula2, in some embodiments R¹¹ is H, F, Cl, Br, CN, OCH₃, CHF₂, CF₃,C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₄ hydroxyalkyl. In some embodiments,R¹¹ is H. With respect to the embodiments recited in this paragraph, insome embodiments, the remaining groups of R¹⁻¹⁸ may independently beR^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₄ hydroxyalkyl, NO₂,NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B),etc. In some embodiments, the remaining groups of R¹⁻¹⁸ may be H, F, Cl,Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation, such as Formula2, in some embodiments R¹² is H, F, Cl, Br, CN, OCH₃, CHF₂, CF₃,C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₄ hydroxyalkyl. In some embodiments,R¹² is H. With respect to the embodiments recited in this paragraph, insome embodiments, the remaining groups of R¹⁻¹⁸ may independently beR^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₄ hydroxyalkyl, NO₂,NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B),etc. In some embodiments, the remaining groups of R¹⁻¹⁸ may be H, F, Cl,Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation, such as Formula2, in some embodiments R¹³ is H, F, Cl, Br, CN, OCH₃, CHF₂, CF₃,C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₄ hydroxyalkyl. In some embodiments,R¹³ is H. With respect to the embodiments recited in this paragraph, insome embodiments, the remaining groups of R¹⁻¹⁸ may independently beR^(A), F, Cl, Br, CN, OR^(A), C₁₋₃ fluoroalkyl, C₁₋₄ hydroxyalkyl, NO₂,NR^(A)R^(B), COR^(A), CO₂R^(A), OCORA, NR^(A)COR^(B), CONR^(A)R^(B),etc. In some embodiments, the remaining groups of R¹⁻¹⁸ may be H, F, Cl,Br, CN, C₁₋₃ fluoroalkyl, OH, NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

With respect to any relevant structural representation, such as Formula2, in some embodiments R¹⁴ is H, F, Cl, Br, CN, OCH₃, CHF₂, CF₃,C₁₋₄—CO₂-alkyl, C₁₋₄ alkyl, or C₁₋₄ hydroxyalkyl. In some embodiments,R¹⁴ is H. In some embodiments, R¹⁴ is F. With respect to the embodimentsrecited in this paragraph, in some embodiments, the remaining groups ofR¹⁻¹⁸ may independently be R^(A), F, Cl, Br, CN, OR^(A), C₁₋₃fluoroalkyl, C₁₋₄ hydroxyalkyl, NO₂, NR^(A)R^(B), COR^(A), CO₂R^(A),OCORA, NR^(A)COR^(B), CONR^(A)R^(B), etc. In some embodiments, theremaining groups of R¹⁻¹⁸ may be H, F, Cl, Br, CN, C₁₋₃ fluoroalkyl, OH,NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₄—CO₂-alkyl, or C₁₋₄ hydroxyalkyl.

Some embodiments include:

The compounds described herein, such as a compound of Formula 1 orFormula 2, (referred to hereafter as a “subject compound” or “subjectcompounds”) can be used to treat a disorder associated with a Kv7potassium channel activator. Treatment of a disorder includes diagnosis,cure, mitigation, treatment, or prevention of the disorder in man orother animals. In some embodiments, the disorder is epilepsy, pain,migraine, a disorder of neurotransmitter release, a smooth musclecontractility disorder, a dyskinesia, dystonia, mania, or a hearingdisorder. In some embodiments, the disorder is epilepsy, neuropathicpain, inflammatory pain, persistent pain, cancer pain, postoperativepain, migraine, anxiety, substance abuse, schizophrenia, a bladderdisorder, a vasculature disorder, a dyskinesia, dystonia, mania, ahearing disorder, or tinnitus.

Appropriate excipients for use in a pharmaceutical compositioncomprising a subject compound (referred to hereafter as “subjectcompositions” or a “subject composition”) may include, for example, oneor more carriers, binders, fillers, vehicles, disintegrants,surfactants, dispersion or suspension aids, thickening or emulsifyingagents, isotonic agents, preservatives, lubricants, and the like orcombinations thereof, as suited to a particular dosage from desired.Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin(Mack Publishing Co., Easton, Pa., 1980) discloses various carriers usedin formulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof.

A subject composition may be formulated for any desirable route ofdelivery including, but not limited to, parenteral, intravenous,intradermal, subcutaneous, oral, inhalative, transdermal, topical,transmucosal, rectal, interacisternal, intravaginal, intraperitoneal,buccal, and intraocular.

Parenteral, intradermal or subcutaneous formulations may be sterileinjectable aqueous or oleaginous suspensions or solutions. Acceptablevehicles, solutions, suspensions and solvents may include, but are notlimited to, water or other sterile diluent; saline; Ringer's solution;sodium chloride; fixed oils such as mono- or diglycerides; fatty acidssuch as oleic acid; polyethylene glycols; glycerine; propylene glycol orother synthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfate;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates; and agents for the adjustment oftonicity such as sodium chloride or dextrose. The pH can be adjustedwith acids or bases, such as hydrochloric acid or sodium hydroxide. Aparenteral preparation may be enclosed in ampoules, disposable syringesor multiple dose vials made of glass or plastic.

Pharmaceutical compositions suitable for injectable use may includesterile aqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersion. For intravenous administration, suitable carriers include,but are not limited to, saline, bacteriostatic water, CREMOPHOR EL®(BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). The solventor dispersion medium may contain, for example, water, ethanol, polyol(for example, glycerol, propylene glycol, and liquid polyethyleneglycol, and the like), and suitable mixtures thereof. Proper fluiditycan be maintained, for example, by the use of a coating such aslecithin, by the maintenance of the required particle size in the caseof dispersion and by the use of surfactants. Preventing growth ofmicroorganisms can be achieved by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, ascorbic acid,thimerosal, and the like. The composition may also include isotonicagents such as, for example, sugars; polyalcohols such as mannitol;sorbitol; or sodium chloride. Prolonged absorption of injectablecompositions can be enhanced by addition of an agent that delaysabsorption, such as, for example, aluminum monostearate or gelatin.

Oral compositions may include an inert diluent or an edible carrier.They may be enclosed in gelatin capsules or compressed into tablets.Tablets, pills, capsules, troches and the like can contain any of thefollowing ingredients, or compounds of a similar nature: a binder suchas microcrystalline cellulose, gum tragacanth or gelatin; an excipientsuch as starch or lactose; a disintegrating agent such as alginic acid,Primogel, or corn starch; a lubricant such as magnesium stearate; aglidant such as colloidal silicon dioxide; a sweetening agent such assucrose or saccharin; or a flavoring agent such as peppermint, methylsalicylate, or orange flavoring.

In addition to oral or injected administration, systemic administrationmay be by transmucosal or transdermal means. For transmucosal ortransdermal administration, penetrants may be used. Such penetrants aregenerally known in the art and include, for example, detergents, bilesalts, and fusidic acid derivatives. Transdermal administration mayinclude a bioactive agent and may be formulated into ointments, salves,gels, or creams as generally known in the art. Transmucosaladministration may be accomplished through the use of nasal sprays orsuppositories.

A subject compound may be administered in a therapeutically effectiveamount, according to an appropriate dosing regimen. As understood by askilled artisan, an exact amount required may vary from subject tosubject, depending on a subject's species, age and general condition,the severity of the infection, the particular agent(s) and the mode ofadministration. In some embodiments, about 0.001 mg/kg to about 50mg/kg, of the pharmaceutical composition based on the subject's bodyweight is administered, one or more times a day, to obtain the desiredtherapeutic effect. In other embodiments, about 0.01 mg/kg to about 25mg/kg, of the pharmaceutical composition based on the subject's bodyweight is administered, one or more times a day, to obtain the desiredtherapeutic effect.

A total daily dosage of a subject compound can be determined by theattending physician within the scope of sound medical judgment. Aspecific therapeutically effective dose level for any particular patientor subject will depend upon a variety of factors including the disorderbeing treated and the severity of the disorder; the activity of thespecific compound employed; the specific composition employed; the age,body weight, general health, sex and diet of the patient or subject; thetime of administration, route of administration, and rate of excretionof the specific compound employed; the duration of the treatment; drugsused in combination or coincidental with the specific compound employed;and other factors well known in the medical arts.

Embodiments Section

The following example embodiments are contemplated.

Embodiment 1. A compound represented by a formula:

wherein D is optionally substituted C₃₋₆ carbocyclyl, optionallysubstituted C₂₋₅ heterocyclyl, isopropyl, or t-butyl;

Bz is optionally substituted benzoimidazol-1,2-diyl;

A is C₁₋₅ alkyl;

X is H, F, CF₃, optionally substituted phenyl, or optionally substitutedpyridinyl; and

Y is H, F, Cl, Br, I, or a moiety having a molecular weight of 15 Da to300 Da and consisting of 2 to 5 chemical elements, wherein the chemicalelements are independently C, H, O, N, S, F, Cl, or Br.

Embodiment 2. The compound of embodiment 1, wherein each substituent ofD, Bz, or X, if present, independently has a molecular weight of 15 Dato 200 Da and consists of 2 to 5 chemical elements, wherein the chemicalelements are independently C, H, O, N, S, F, Cl, or Br.Embodiment 3. The compound of embodiment 1 or 2, wherein Y is H, F, Cl,Br, I, CN, —COH, C₁₋₆—CO-alkyl, CF₃, OH, C₁₋₅ O-alkyl, C₀₋₆ amino, orC₀₋₆ fluoroamino.Embodiment 4. The compound of embodiment 1, 2, or 3, further representedby a formula:

wherein R¹, R², R³, and R⁴ are independently H, F, Cl, Br, I, or asubstituent having a molecular weight of 15 Da to 200 Da and consistingof 2 to 5 chemical elements, wherein the chemical elements areindependently C, H, O, N, S, F, Cl, or Br.

Embodiment 5. The compound of embodiment 1, 2, 3, or 4, wherein Y is H,F, CF₃, OH, C₁₋₅ O-alkyl, C₀₋₆ alkylamino, optionally substitutedtetrahydropyranyl, or C₀₋₆ fluoroalkylamino.

Embodiment 6. The compound of embodiment 4 or 5, wherein R¹ is H, Cl,Br, —OCH₃, —CN, —CF₃, —CH₂OH, —COOCH₂CH₃, —C(CH₃)₂OH, —CHOHCH₂CH₃,—CHOHCH₃, —CHF₂, —CH(CH₃)₂, —C(CH₂CH₃)OH, —CH₂COOCH₂CH₃, —CH₂C(CH₃)₂OH,—CH₂COOH, or —CH₂CON(CH₃)₂.

Embodiment 7. The compound of embodiment 4, 5, or 6, wherein R² is H, F,—CH₂OH, —CO₂Me, or —C(CH₃)₂OH.

Embodiment 8. The compound of embodiment 4, 5, 6, or 7, wherein R³ is H.

Embodiment 9. The compound of embodiment 4, 5, 6, 7, or 8, wherein R⁴ isH, —CH₃, or —CF₃.

Embodiment 10. The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, or 9,wherein D is optionally substituted cyclobutyl, optionally substitutedphenyl, optionally substituted isoxazolyl, optionally substitutedpyridinyl, isopropyl, or t-butyl.

Embodiment 11. The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, or10, wherein each substituent of D, X, and Y, if present, independentlyhas a molecular weight of 15 Da to 200 Da and consists of 2 to 5chemical elements, wherein the chemical elements are independently C, H,O, N, S, F, Cl, or Br.Embodiment 12. The compound of embodiment 4, 5, 6, 7, 8, 9, 10, or 11,wherein R¹ is H, Cl, Br, CN, OCH₃, CF₃, —CO₂CH₂CH₃, C₁₋₄ alkyl, or C₁₋₄hydroxyalkyl.Embodiment 13. The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, or 12, wherein D is optionally substituted cyclobutyl.Embodiment 14. The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, or 12, wherein D is cyclobutyl.Embodiment 15. The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, or 12, wherein D is optionally substituted phenyl.Embodiment 16. The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, or 12, wherein D is optionally substituted isoxazolyl.Embodiment 17. The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, or 12, wherein D is isopropyl.Embodiment 18. The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, or 12, wherein D is t-butyl.Embodiment 19. The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, or 12, wherein D is optionally substituted pyridinyl.Embodiment 20. The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, or 19, wherein X is optionallysubstituted phenyl.Embodiment 21. The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, or 19, wherein X is CF₃.Embodiment 22. The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, or 19, wherein X is F.Embodiment 23. The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, or 19, wherein X is optionallysubstituted pyridinyl.Embodiment 24. The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, or 19, wherein X is H.Embodiment 25. The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, wherein Y isH.Embodiment 26. The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, wherein Y isOH.Embodiment 27. The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, wherein Y isF.Embodiment 28. The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, wherein Y isCF₃.Embodiment 29. The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, wherein Y isC₁₋₃ O-alkyl.Embodiment 30. The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, wherein Y isC₀₋₆ fluoroamino.Embodiment 31. The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, wherein Y isdimethylamino.Embodiment 32. The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, wherein Y ismethyl(2,2,2-trifluoroethyl)amino.Embodiment 33. The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, wherein Y isoptionally substituted tetrahydropyranyl.Embodiment 34. The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, wherein Y is1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl.Embodiment 35. The compound of embodiment 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,31, 32, 33, or 34, wherein A is C₂₋₈ alkyl; and wherein at least one ofR¹, R², R³, and R⁴ are independently F, Cl, Br, I, or a substituenthaving a molecular weight of 15 Da to 200 Da and consisting of 2 to 5chemical elements, wherein the chemical elements are independently C, H,O, N, S, F, Cl, or Br.Embodiment 36. A compound represented by a formula:

Embodiment 37. A composition comprising a compound of embodiment 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein thecomposition is pharmaceutically acceptable.Embodiment 38. A pharmaceutical dosage form comprising a compound ofembodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,or 36.Embodiment 39. A method of treating a disorder associated with a Kv7potassium channel activator comprising administering an effective amountof a compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35, or 36, to a mammal in need thereof.Embodiment 40. The method of embodiment 39, wherein the disorder isepilepsy, pain, migraine, a disorder of neurotransmitter release, asmooth muscle contractility disorder, a dyskinesia, dystonia, mania, ora hearing disorder.Embodiment 41. The method of embodiment 39, wherein the disorder isepilepsy, neuropathic pain, inflammatory pain, persistent pain, cancerpain, postoperative pain, migraine, anxiety, substance abuse,schizophrenia, a bladder disorder, a vasculature disorder, a dyskinesia,dystonia, mania, a hearing disorder, or tinnitus.Embodiment 42. Use of a compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, in the manufacture of amedicament for the treatment of a disorder associated with a Kv7potassium channel activator.Embodiment 43. The use of embodiment 42, wherein the disorder isepilepsy, pain, migraine, a disorder of neurotransmitter release, asmooth muscle contractility disorder, a dyskinesia, dystonia, mania, ora hearing disorder.Embodiment 44. The use of embodiment 42, wherein the disorder isepilepsy, neuropathic pain, inflammatory pain, persistent pain, cancerpain, postoperative pain, migraine, anxiety, substance abuse,schizophrenia, a bladder disorder, a vasculature disorder, a dyskinesia,dystonia, mania, a hearing disorder, or tinnitus.

Experimental Section

Scheme 1 shows a general methodology for the synthesis of1H-benzo[d]imidazol-2-yl amides 1.5. An appropriately substituted1-fluoro-2-nitrobenzene 1.1 is reacted with a primary amine to afford1-amino-2-nitrobenzene 1.2. Alternatively, a 1-chloro-2-nitrobenzene isreacted with a primary amine under palladium catalysis to provide thedesired 1-amino-2-nitrobenzene 1.2. The nitro group may be reduced tothe corresponding amine by a variety of well-established methods toprovide 1,2-diaminobenzenes 1.3. Reaction of 1.3 with cyanogen bromideaffords 1H-benzo[d]imidazol-2-amines 1.4. Amide coupling with either anappropriate carboxylic acid or acyl chloride can afford1H-benzo[d]imidazol-2-yl amides such as 1.5.

Scheme 2 and Scheme 3 describe general methodologies that may be used tocreate novel Kv7 modulators after the initial amide bond formingreaction has been used to synthesize 1H-benzo[d]imidazol-2-yl amidessuch as 2.3. Sulfuric acid-promoted ethanolysis of the nitrile in2-amino-1-cyclobutyl-1H-benzo[d]imidazole-6-carbonitrile (2.1) gives theethyl ester 2.2. This amino-heterocycle may be used as the amine in astandard amide bond forming reaction to give the ester amide 2.3. Theethyl ester may serve as a synthetic handle to access various otherfunctional groups. The ester may be reduced with DiBAL-H to the primaryalcohol 2.4. Alternatively, excess Grignard reagent may be used togenerate a tertiary alcohol 2.7. The primary alcohol 2.4 may be readilyoxidized with the Dess-Martin periodinane or a similar oxidant togenerate an intermediate aldehyde 2.5. The aldehyde 2.5 may serve as theinput for a difluorination reaction, for example using Xtal-FluorEreagent, to provide the difluoromethyl-substituted amides 2.6 (seeCouturier, M, et al, J. Org. Chem. 2010, 75, 3401-3411). The tertiaryalcohols 2.7 may be reduced under the action of triethylsilane andtrifluoroacetic acid in dichloromethane to give the branched benzylicalkyl groups present in amides 2.8. It is noteworthy that the newmolecules 2.4-2.8 are convenient as intermediates for further conversioninto additional benzo-ring substituents, such as amides, ethers, andheterocycles, using known methodologies.

A range of functional groups may be orthogonally transformed in thepresence of the amide functionality of 1H-benzo[d]imidazol-2-yl amides.Scheme 3 shows how the nitrile 3.1 may be selectively reacted with aGrignard reagent to produce an aryl ketone 3.2. This ketone may bereduced with common hydride reagents, such as sodium borohydride, togive the secondary alcohol 3.3. Such ketone reductions may be conductedin a stereochemically-defined manner, using a variety of chiral reducingreagents known in the literature (e.g. via CBS reagent, see Corey, E J,Shibata, S, Bakshi, R K, J. Org. Chem. 1988, 53, 2861-2863).

The general methodology of Scheme 1 may be used to synthesize a widerange of functionalized 1H-benzo[d]imidazol-2-yl amides. Bromide 4.1 inScheme 4 is an example of a halogenated-1H-benzo[d]imidazol-2-yl amidethat also provides an orthogonally reactive functional group. Thebromide may be reduced with the action of triethylsilane in chloroformand methanol with a catalytic amount of palladium on charcoal to givethe debrominated product 4.2 (see Mandal, P K, McMurray, J S, J. Org.Chem. 2007, 72, 6599-6601). The aromatic bromide in 4.1 may also be usedto perform palladium cross coupling reactions such as Sonogashira,Suzuki, or Stille reactions to provide alkynes, biaryl or other crosscoupled products.

Scheme 5 describes a general synthetic method for the synthesis ofchiral α-alkyl carboxylic acids that contain β-silyloxy ether protectedacids 5.4 or ent-5.4. These optically active acids are used as the acidcomponent in amide forming reaction (Step D of Scheme 1) to giveβ-tertiary alcohol amides. The diastereoselective bond construction viatitanium enolate chemistry described by Evans was used to condensechiral imide 5.1 or ent-5.1 with a ketone or other electrophile to givediastereomerically pure aldol adducts 5.2 or ent-5.2, respectively (seeEvans, D A, Urpi, F, Somers, T C, Clark, J S, Bilodeau, M T, J. Am.Chem. Soc. 1990, 112, 8215-8216). The proper choice of chiral imide 5.1will give rise to the desired absolute stereochemistry of theα-stereocenter in the carboxylic acids 5.4 or ent-5.4. Silyl etherprotection of the aldol adducts 5.2 and ent-5.2 withtert-butyldimethylsilyltriflate and diisopropylethylamine gives thetert-butyldimethylsilyl ethers 5.3 and ent-5.3. Standard acyloxazolidinone hydrolysis conditions using lithium hydroxide and hydrogenperoxide in tetrahydrofuran and water provides the desired acids 5.4 orent-5.4 (see Evans, D A, Britton, T C, Ellman, J A, Tetrahedron Lett.1987, 28(49), 6141-6144). Proper selection of ketones or otherelectrophiles in the titanium enolate chemistry will give rise toappropriately substituted aldol adducts that vary in the nature of theR₂ and R₃ groups. Changing the R₁ group of the starting imides 5.1 andent-5.1 may be used to vary the size and nature of the R₁ group in theacids 5.4 or ent-5.4. This methodology allows one to synthesize a widerange of optically active acids with absolute stereocontrol of theα-chiral center to the carbonyl of the carboxylic acid.

A general synthetic method for the synthesis of enantiomerically pureα-methyl-β-branched chiral carboxylic acids 6.4 or ent-6.4 is describedin Scheme 6. Both of the enantiomerically pure oxazolidinones(S)-4-benzyloxazolidin-2-one 6.1 and (R)-4-benzyloxazolidin-2-oneent-6.1 are commercially available. These oxazolidinones may be readilyacylated by deprotonation with n-butyl lithium followed by reaction withacid chlorides 6.5 to give the chiral imides 6.2 and ent-6.2,respectively. There are a large number of commercially available acidchlorides 6.5 with wide variation about the R₁, R₂ and R₃ groups of thisinput. This allows for the rapid synthesis of chiral imides 6.2 andent-6.2 that have differing substitution at the β-position to theexocyclic carbonyl group. The asymmetric alkylation reaction of chiralimide sodium enolates as developed by Evans may then be used tointroduce a methyl group in a stereoselective fashion (see Evans, D A,Ennis, M D, Mathre, D J, J. Am. Chem. Soc. 1982, 104, 1737-1739). Thesodium enolate of imide 6.2 may be produced by treatment of 6.2 withsodium hexamethyldisilazide in tetrahydrofuran. The resultant sodiumenolate may then be stereoselectively methylated by the addition ofmethyl iodide. The pure and single diastereomers 6.3 and ent-6.3 may beisolated by silica gel column chromatography. Alternatively, the singlediastereomers may be obtained by recrystallization of crystallineproducts 6.3 and ent-6.3. The well-known chiral auxiliary hydrolysisconditions as described above for Scheme 5 give the optically activeα-methyl β-branched chiral carboxylic acids 6.4 or ent-6.4,respectively.

Scheme 7 shows a general methodology for the synthesis of3-hydroxypropanoic acids such as 7.3. An appropriately substituted2-bromoethanoic ester 7.1 is reacted with a ketone or aldehyde to afford3-hydroxypropanoic esters 7.2. The ester group may be hydrolyzed to thecorresponding acid by saponification to provide 3-hydroxypropanoic acidssuch as 7.3.

Scheme 8 depicts additional methods for the preparation of optionallysubstituted 3-hydroxypropanoic acids. An appropriately substituted3-acetyloxazolidin-2-one 8.1 is reacted with a ketone or aldehyde toafford 3-(3-hydroxypropanoyl)oxazolidin-2-ones 8.2. The hydroxyl groupis functionalized with a protecting group to provide diastereomers 8.3that are separable by silica gel chromatography. Each diastereomer 8.3is then reacted in a two-step sequence, in either order, of hydroxylgroup deprotection and oxazolidinone cleavage to provide3-hydroxypropanoic acids such as 8.6.

Scheme 9 describes methods that can be applied to the syntheses of aminoacid substituted 1H-benzo[d]imidazol-2-yl) amides such as 9.4.Appropriately substituted 1H-benzo[d]imidazol-2-amines 9.1 may becoupled with carbamate-protected amino acid derivatives such as 9.2 toafford the corresponding amides 9.3. The carbamate protecting group canbe removed from the amine via one of a number of strongly acidicreagents to afford amines like 9.4. Such secondary amines can then befurther functionalized under standard amine alkylation conditions toprovide tertiary amine-containing 1H-benzo[d]imidazol-2-yl)amides suchas such as 9.5.

Scheme 10 describes methods that can be employed to prepare1H-benzo[d]imidazol-2-yl)amides substituted with hydroxyl-containingamides such as 10.4. Appropriately substituted1H-benzo[d]imidazol-2-amines 10.1 may be coupled with protected alcoholderivatives such as 10.2 to afford the corresponding amides 10.3. Thealcohol protecting group can be removed via several methods includingtetrabutylammonium fluoride to provide alcohol-containing1H-benzo[d]imidazol-2-yl) amides such as such as 10.4.

Synthetic Methods

Section 1. Representative Procedures for the Preparation of1H-benzo[d]imidazol-2-amines Intermediates (Compounds 1.4, Scheme 1).

Method 1

Step A. Preparation of 3-(cyclobutylamino)-4-nitrobenzonitrile

A 500 mL round-bottom flask was charged with of3-fluoro-4-nitrobenzonitrile (5.00 g, 30.1 mmol) and tetrahydrofuran(100 mL) and placed in a 0° C. bath. After 5 minutes, cyclobutylaminehydrochloric acid (3.60 g, 33.0 mmol) was added in one portion withstirring before the dropwise addition of diisopropylethylamine (15 mL,82 mmol). The mixture was allowed to stir at 0° C. for 1 hour. The icebath was removed and the flask was allowed to warm to room temperatureand allowed to stir overnight. The bulk of the tetrahydrofuran wasremoved on a rotary evaporator before the mixture was diluted with EtOAc(200 mL). The organic layer was washed with saturated aqueous ammoniumchloride twice, saturated aqueous sodium bicarbonate, and brine and thendried over anhydrous sodium sulfate. The dried solution was filtered andconcentrated to give the desired product as a crude orange solid (6.25g). TLC R_(f)=0.70-0.45 streak in 20% EtOAc in hexanes. MS (ESI) m/z218.0 (MH⁺). ¹H NMR (CDCl₃): δ 8.24 (d, J=8.68 Hz, 1H), 8.11 (bs, 1H),7.01 (d, J=1.48 Hz, 1H), 6.86 (dd, J=8.72, 1.64, 1H), 4.09-4.00 (m, 1H),2.60-2.51 (m, 2H), 2.11-1.88 (m, 4H).

Step B. Preparation of 4-amino-3-(cyclobutylamino) benzonitrile

To a solution of 3-(cyclobutylamino)-4-nitrobenzonitrile (6.50 g, 30.1mmol) in EtOH (160 mL) was added iron powder (8.8 g, 150 mmol) and asolution of ammonium chloride (8.1 g, 150 mmol) in water (30 mL). Themixture was heated in a sand bath at 90° C. for 16 hours while beingexposed to air. The mixture was allowed to cool, diluted with EtOAc (200mL) and the resulting mixture was filtered through Celite. The Celitewas rinsed with saturated aqueous sodium bicarbonate and EtOAc. Thecombined filtrates were separated and the aqueous layer was extractedwith EtOAc. The combined organics were washed with brine, dried withanhydrous sodium sulfate and concentrated to provide the crude titlecompound (6.2 g). The material was subjected to a 120 g Isco silica gelcolumn (10 to 40% EtOAc in hexanes) to provide the desired product (4.17g) in a 74% yield for two steps as a pink colored solid. MS (ESI) m/z188.0 (MH⁺). ¹H NMR (CDCl₃): δ 7.01 (dd, J=8.00, 1.76 Hz, 1H), 6.73 (d,J=1.72 Hz, 1H), 6.68 (d, J=8.0 Hz, 1H), 3.92-3.85 (m, 1H), 3.65-3.45 (brm, 2H), 2.53-2.44 (m, 2H), 1.88-1.83 (m, 4H).

Step C. Preparation of2-amino-1-cyclobutyl-1H-benzo[d]imidazole-6-carbonitrile

To a solution of 4-amino-3-(cyclobutylamino) benzonitrile (4.0 g, 21.3mmol) in EtOH (100 mL) was added a solution of cyanogen bromide (3 M inCH₂Cl₂, 14 mL, 42 mmol. The mixture was stirred at room temperature for18 hours and then concentrated in vacuo. The residue was partitionedbetween EtOAc (150 mL) and aqueous Na₂CO₃ (10%, 100 mL). The aqueouslayer was extracted twice with EtOAc. The combined organic layers werewashed with brine, dried (Na₂SO₄) and concentrated to give a pink solid(4.5 g). The solid was subjected to a hexanes and EtOAc trituration toprovide the title compound as a pale pink solid (3.1 g, 69%). R_(f)=0.1streak in 100% EtOAc. MS (ESI) m/z 213.2 (MH⁺). ¹H NMR (MeOH-d₄): δ 7.78(s, 1H), 7.38 (d, J=8.28, 1H), 7.28 (d, J=8.20, 1H), 4.92-4.81 (m, 1H),2.88-2.78 (m, 2H), 2.54-2.45 (m, 2H), 2.08-1.78 (m, 2H). An additionalportion of the desired product (1.0 g) was recovered from thetrituration solvent and showed to be desired product with >90% purity by¹H NMR.

The following 1H-benzo[d]imidazol-2-amines were prepared using thegeneral procedures described in Section 1, Method 1, with appropriatestarting materials. Alternative procedures for certain startingmaterials are described in the Methods 2-5.

1-cyclobutyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-amine

6-bromo-1-cyclobutyl-1H-benzo[d]imidazol-2-amine

1-isopropyl-6-methoxy-1H-benzo[d]imidazol-2-amine

methyl 2-amino-1-cyclobutyl-1H-benzo[d]imidazole-7-carboxylate

2-amino-1-(tert-butyl)-1H-benzo[d]imidazole-6-carbonitrile

2-amino-1-(1-methylcyclobutyl)-1H-benzo[d]imidazole-6-carbonitrile

6-chloro-1-(4-fluorophenyl)-1H-benzo[d]imidazol-2-amine

2-amino-1-cyclobutyl-5-methyl-1H-benzo[d]imidazole-6-carbonitrile

2-amino-1-(tert-butyl)-5-methyl-1H-benzo[d]imidazole-6-carbonitrile

1-cyclobutyl-7-fluoro-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-amine

1-(4-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-amine

1-(3,5-difluorophenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-amine

2-amino-1-(5-fluoropyridin-2-yl)-1H-benzo[d]imidazole-6-carbonitrile

1-(3,4-difluorophenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-amine

1-(3-fluoro-4-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-amine

1-(4-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-amine

ethyl 2-(2-amino-1-cyclobutyl-7-fluoro-1H-benzo[d]imidazol-6-yl)acetate

ethyl2-(2-amino-7-fluoro-1-(4-fluorophenyl)-1H-benzo[d]imidazol-6-yl)acetate

Method 2: Preparation of 3-((4-fluorophenyl)amino)-4-nitrobenzonitrilefor Use in Method 1, Step B

A mixture of 3-fluoro-4-nitrobenzonitrile (2 g, 12 mmol), triethylamine(1.7 mL, 1.5 equivalents) and 4-fluoroaniline (1.7 mL, 1.5 equivalents)was heated at 60° C. under a nitrogen atmosphere for 60 hours. Theresulting solid red-brown mass was cooled to ambient temperature andsuspended in 50 mL of 1 N aqueous hydrochloric acid. The mixture wasextracted extensively with dichloromethane and the organic extractsdried over anhydrous magnesium sulfate. Concentration of the organicextracts under reduced pressure afforded 2.9 g of a red solid,practically pure by LC/MS. MS (ESI) m/z 256 (M-H⁻).

Method 3: Preparation of 5-chloro-N-cyclobutyl-2-nitroaniline for Use inMethod 1, Step B

A mixture of cyclobutylamine hydrochloride (2.15 g), triethylamine (2.8mL), 2,4-dichloro-1-nitrobenzene (3.84 g, 20 mmol, limiting reagent) andtetrahydrofuran (40 mL) was heated in a sealed vial at 100° C. for 16hours. The reaction mixture was cooled to room temperature, and 0.2equivalents of both cyclobutylamine hydrochloride and triethylamineadded, and the resulting mixture was heated at 100° C. for an additional17 hours. The cooled reaction mixture was diluted with water, extractedthoroughly with dichloromethane and ethyl acetate, the organic extractsdried over anhydrous magnesium sulfate and concentrated. Purification ofthe crude product by chromatography on silica with 20% dichloromethanein hexanes as eluent afforded the desired product (1.65 g) as an orangesolid. ¹H NMR (CDCl₃): δ 8.16 (NH, bs), 8.12 (1H, d), 6.70 (1H, s), 6.60(1H, d), 4.02 (1H, m), 2.53 (2H, m), 2.03 (2H, m), 1.92 (2H, m).

Method 4: Preparation of3-Methyl-N-(2-nitro-5-(trifluoromethyl)phenyl)isoxazol-5-amine for Usein Method 5

Palladium(II) acetate (1.00 g, 0.443 mmol) was added to Xantphos (0.513g, 0.887 mmol) in degassed dioxane (10 mL) and the suspension wasstirred for 15 minutes under N₂. The resulting solution was added to amixture of 2-chloro-3-nitro-6-(trifluoromethyl)benzene (1.00 g, 4.43mmol), 3-methylisoxazol-5-amine (0.522 g, 5.32 mmol) and K₂CO₃ (0.919 g,6.65 mmol) in degassed dioxane (40 mL) and the reaction mixture wasrefluxed overnight. Conversion was confirmed by TLC and the solution wasfiltered through a plug of celite. The volatiles were removed and thecrude residue was purified by chromatography on silica (0-100%EtOAc/hexanes) to give 0.811 g (63%) of the title compound. MS (ESI) m/z288 (MH⁺).

The following intermediates were prepared for use in Method 1, Step Busing the general procedure described in Section 1, Method 4, withappropriate starting materials.

-   3-((5-fluoropyridin-2-yl)amino)-4-nitrobenzonitrile-   N-(3,5-difluorophenyl)-2-nitro-5-(trifluoromethyl)aniline-   N-(3-fluoro-4-(trifluoromethoxy)phenyl)-2-nitro-5-(trifluoromethyl)aniline-   2-nitro-N-(4-(trifluoromethoxy)phenyl)-5-(trifluoromethyl)aniline-   N-(3,4-difluorophenyl)-2-nitro-5-(trifluoromethyl)aniline

Method 5: Preparation ofN¹-(3-methylisoxazol-5-yl)-5-(trifluoromethyl)benzene-1,2-diamine foruse in Method 1, Step C

Sodium bicarbonate (0.410 g, 4.88 mmol) then sodium hydrosulfite (1.27g, 7.31 mmol) were added to a solution of the nitro aromatic core (0.700g, 2.44 mmol) in tetrahydrofuran:H₂O (2:1; 24 mL). The resultingreaction mixture was allowed to stir for 4 hours, diluted with H₂O andthen extracted with EtOAc. The combined organics were dried (MgSO₄) andthe volatiles removed to leave a crude residue that was purified bychromatography on silica (0-5% MeOH/dichloromethane) to give 380 mg(61%) of the title compound. MS (ESI) m/z 258 (MH⁺).

The following benzene-1,2-diamine was prepared using the generalprocedures described in Section 1, Methods 4 and 5, with appropriatestarting materials, for use in Method 1, Step C:

4-amino-3-((3-methylisoxazol-5-yl)amino)benzonitrile

Method 6: Preparation of ethyl2-amino-1-cyclobutyl-1H-benzo[d]imidazole-6-carboxylate

To a solution of 4-amino-3-(cyclobutylamino) benzonitrile (1.5 g, 7.0mmol) in EtOH (30 mL) was added water (3 mL) and concentrated sulfuricacid (3 mL). The solution was placed in a 150° C. sand bath withstirring for 4 days. The reaction was allowed to cool to ambienttemperature and carefully quenched by pouring slowly into saturatedaqueous sodium bicarbonate. The mixture was diluted with EtOAc and thelayers were separated. The aqueous layer was back extracted withdichloromethane and the combined organic layers were washed with brine,dried with sodium sulfate, filtered and concentrated to give the titlecompound as a tan solid (790 mg, 43% yield). MS (ESI) m/z 260.0 (MH⁺),retention time=2.21 min (Method B).

Section 2. Representative Procedures for the Preparation of1H-benzo[d]imidazol-2-yl amides (1.5, Scheme 1).

Method 7: General Procedure for Amide Formation Using HATU(1-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazole3-oxide hexafluorophosphate(V)) as Coupling Reagent

The appropriate carboxylic acid was dissolved in dimethyformamide or THF(0.20-0.7 M) and diisopropylethylamine or pyridine (2 equivalents) wasadded prior to the addition of1-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazole3-oxide hexafluorophosphate(V) (HATU, 1.2 equivalents) in one portion.The reaction was allowed to stir at room temperature for 0 to 15 minutesprior to the addition of the required substituted 2-aminobenzimidazole(1 equivalent) and the flask was placed in a heated sand bath (40-65°C.) for 8 to 48 hours. The mixture was diluted with EtOAc and washedsequentially with saturated aqueous NH₄Cl (2×), saturated aqueous NaHCO₃(2×), 10% aqueous Na₂CO₃ (2×), and brine. The organic layer was driedover Na₂SO₄ and concentrated. Purification by by chromatography onsilica (0-100% EtOAc/hexanes or 0-10% MeOH/dichloromethane) provided thetitle corresponding 1H-benzo[d]imidazol-2-yl amides.

Method 8: General Procedure for Amide Formation Using Acyl Chlorides

To a solution appropriate 1H-benzo[d]imidazol-2-amine intermediate (0.22mmol) in tetrahydrofuran (1 mL) was added pyridine (1.5 equivalents) andacyl chloride (1.2 equivalents). The reaction mixture was stirred for 18hours. The mixture was partitioned between EtOAc and water. The organiclayer was dried (Na₂SO₄) and concentrated. The residue was purified bychromatography on silica (0-100% EtOAc/hexanes) to provide titlecompounds.

Method 9: General Procedure for Amide Coupling Using Excess AcidChloride Followed by Treatment with Ammonia Example 46. Preparation of3,3-dimethyl-N-(1-(3-methylisoxazol-5-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)butanamide

3,3-Dimethylbutanoyl chloride (0.187 mL, 1.04 mmol) was added dropwiseto a 0° C. solution of1-(3-methylisoxazol-5-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-amine(0.030 g, 0.104 mmol) and triethylamine (0.180 mL, 1.56 mmol) in CH₂Cl₂(1 mL) and the reaction mixture was allowed to warm to ambienttemperature and stir for 30 minutes. Ammonia (2.0 M in MeOH, 1 mL) wasadded and the mixture was stirred at 50° C. for two hours beforequenching with saturated aqueous NH₄Cl. The aqueous portion wasextracted with EtOAc, the combined organics were dried (MgSO₄) and thevolatiles removed to give a crude residue that was purified bychromatography on silica (0-5% MeOH/DCM) to yield 0.017 g (43%) of thetitle compound. MS (ESI) m/z 381 (MH⁺).

Method 10: General Procedure for Amide Formation Using EDC(1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) and HOBt(1-hydroxybenzotriazole) as coupling reagents

A solution of the appropriate 1H-benzo[d]imidazol-2-amine (0.13 mmol),carboxylic acid (0.16 mmol), EDC (0.19 mmol), HOBt (0.19 mmol) anddiisopropylethylamine (0.66 mmol) in tetrahydrofuran (1 mL) was heatedat 50° C. under nitrogen for 2-4 hours. The reaction was cooled to roomtemperature, diluted with EtOAc and washed with water. The organicsolution was concentrated in vacuo and purified by flash columnchromatography (silica gel, 0-10% MeOH/DCM) to afford the titlecompounds.

Method 11: Representative Procedure for Amide Formation Using YamaguchiConditions Example 45. Preparation of(S)-2,2-Dimethyl-N-(1-(3-methylisoxazol-5-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)cyclopropanecarboxamide

(S)-2,2-Dimethylcyclopropyl carboxylic acid (0.018 g, 0.159 mmol),triethylamine (0.042 mL, 0.318 mmol) and 2,4,6-trichlorobenzoyl chloride(0.025 mL, 0.159 mmol) was stirred in 1 mL tetrahydrofuran for 30minutes.1-(3-Methylisoxazol-5-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-amine(0.030 g, 0.106 mmol) and 4-(dimethylamino)pyridine (0.003 g, 0.026mmol) were added to the reaction mixture and the resulting solution washeated to 50° C. and stirred overnight. The reaction was quenched withH₂O, extracted (EtOAc 3×) and the combined organics were dried (MgSO₄)and the volatiles removed to give a crude product that was purified bychromatography on silica (0-100% EtOAc/hexanes) followed by HPLC (0-100%MeCN/H₂O) to yield 21 mg (71%) of the desired product. MS (ESI) m/z 379(MH⁺).

Method 12: General Procedure for Amide Formation UsingAcylbenzotriazoles

A solution of appropriate 1H-benzo[d]imidazol-2-amine intermediate (0.66mmol) and triethylamine (0.5 mL, 3.3 mmol, 5 equivalents) intetrahydrofuran (3 mL) was stirred for 5 min at room temperature. Tothis solution was added a solution of an appropriate acylbenzotriazole(0.7 M in dichloromethane, 3.0 mL, 2.0 mmol, 3 equivalents; seeKatritzky, A R, et al, Synlett, 2005, 11, 1656) and the mixture wasplaced in a 50° C. sand bath for 12 hours. The mixture was allowed tocool to room temperature and diluted with EtOAc (50 mL) and washedsequentially with saturated aqueous Na₂CO₃ (three times) and brine. Theorganic layer was dried over Na₂SO₄ and concentrated. Purification bychromatography on silica (0-100% EtOAc/hexane or 0-10%MeOH/dichloromethane) provided the title compounds.

Section 3. Exemplary Syntheses for Examples in Table 1 Involving FurtherTransformation of 1H-benzo[d]imidazol-2-yl amides.

Example 51. Preparation ofN-(1-cyclobutyl-6-(hydroxymethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide

A CH₂Cl₂ (15 mL) solution of ethyl1-cyclobutyl-2-(3,3-dimethylbutanamido)-1H-benzo[d]imidazole-6-carboxylate(112 mg) was placed in a −78° C. bath for 10 minutes prior to thedropwise addition of diisobutylaluminum hydride (1.0 M in CH₂Cl₂, 2 mL).The reaction was allowed to stir at −78° C. for 1 h before beingquenched by the dropwise addition of MeOH (2 mL). The quenched reactionwas diluted with CH₂Cl₂ (50 mL) and sodium/potassium tartrate (1 M, 50mL) was added and the mixture was allowed to vigorously stir overnight.In this time frame, two clear layers developed and the aqueous portionwas extracted with CH₂Cl₂ (2×), the combined organics were washed withbrine, dried (Na₂SO₄) and the volatiles removed to give a crude residuethat was purified via chromatography (Isco 12 g silica gel column, 0-10%MeOH/CH₂Cl₂) to yield 56 mg (57%) of the title compound. MS (ESI) m/z316.4 (MH⁺), retention time=2.35 min. The material was further purifiedby subjecting to another Isco 12 g silica gel column (40 to 100% EtOAcin hexanes) to give 10 mg of the title compound.

Example 53. Preparation ofN-(1-cyclobutyl-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide

A tetrahydrofuran (2 mL) solution of ethyl1-cyclobutyl-2-(3,3-dimethylbutanamido)-1H-benzo[d]imidazole-6-carboxylate(50 mg, 0.14 mmol) was allowed to chill at 0° C. for 10 minutes undernitrogen prior to the dropwise addition of methylmagnesium bromide (2 Min ether, 0.3 mL). The reaction was allowed to stir at 0° C. for 1.5hours and then quenched by the addition of saturated sodium bicarbonate(25 mL) and EtOAc (25 mL). The aqueous layer was extracted twice withEtOAc and the combined organics were washed with brine, dried withsodium sulfate, filtered and concentrated to give a crude residue. Thecrude material was subjected to column chromatography (two 4 g silicagel Isco columns in series, 5 to 50% EtOAc in hexanes) to give the titlecompound as a white solid (16 mg, 33% yield). MS (ESI) m/z 344.4 (MH⁺),retention time=2.44 minutes (Method B).

Example 57. Preparation ofN-(1-cyclobutyl-6-(1-hydroxyethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide

Step A

A tetrahydrofuran (2 mL) solution ofN-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide(112 mg) was placed in a 0° C. bath for 10 minutes prior to the dropwiseaddition of ethylmagnesium bromide (3 M in diethyl ether, 0.45 mL). Thereaction was allowed to stir at 0° C. for 1 h and then allowed to warmup to room temperature. The reaction was allowed to stir at roomtemperature overnight and then placed back in a 0° C. bath for 10minutes before it was quenched with MeOH (0.5 mL). After 5 minutes, thequenched reaction was partioned between saturated aqueous ammoniumchloride (25 mL) and ethyl acetate (25 mL). The aqueous layer wasextracted twice with ethyl acetate. The combined organics were washedwith brine and dried with sodium sulfate. The dried reaction wasfiltered, concentrated and subjected to a 12 g silica gel Isco column(15 to 100% EtOAc in hexanes) to give the ethyl ketone compoundN-(1-cyclobutyl-6-propionyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide(75 mg, 70%) as a white solid. MS (ESI) m/z 342.4 (MH⁺), retentiontime=3.51 minutes (Method B).

Step B

N-(1-Cyclobutyl-6-propionyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide(41 mg) was placed in a roundbottom flask with ethanol (6 mL) and theflask was allowed to chill in a 0° C. bath for 10 minutes before theportionwise addition of sodium borohydride (60 mg). The reaction wasallowed to stir for 30 minutes and then quenched by the slow addition ofHCl (1.0 M, 10 mL). The quenched reaction was diluted with EtOAc (30 mL)and allowed to stir for 1 hour. The aqueous layer was extracted withEtOAc (2×). The combined organics were washed with saturated aqueoussodium bicarbonate (40 mL), brine and dried with sodium sulfate. Thedried solution was filtered and concentrated to give a crude materialthat was subjected to a 12 gram silica gel Isco column (20-50% EtOAc inhexanes) to give the title compound (25 mg, 60%) as a white solid. MS(ESI) m/z 344.4 (MH⁺), retention time=2.57 minutes (Method B).

Example 65. Preparation of(S)—N-(1-cyclobutyl-6-isopropyl-1H-benzo[d]imidazol-2-yl)-2,3-dimethylbutanamide

Solid(S)—N-(1-cyclobutyl-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2,3-dimethylbutanamide(15 mL) was dissolved in dichloromethane (2 mL). TFA (1.5 mL) was addedbefore the dropwise addition of neat triethylsilane (1 mL). The reactionwas allowed to stir overnight and then diluted with dichloromethane (15mL) and washed with saturated sodium bicarbonate (20 mL). The aqueouslayer was extracted twice with dichloromethane. The combined organicswere washed with brine and dried with sodium sulfate. The dried solutionwas filtered and concentrated to give a crude product. The crudematerial was subjected to a high vacuum for 48 h prior to beingsubjected to column chromatography (4 gram Isco silica gel, 0-5% MeOH indichloromethane) to give the title compound as a colorless oil (9 mg,63% yield). MS (ESI) m/z 328.4 (MH⁺), retention time=3.36 min (MethodB).

Example 66. Preparation ofN-(1-cyclobutyl-6-(difluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide

Step A

SolidN-(1-cyclobutyl-6-(hydroxymethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide(100 mg) was dissolved in dichloromethane (5 mL) and solid sodiumbicarbonate (106 mg, 4 equivalents) was added in one portion before theaddition of Dess-Martin periodinane (270 mg, 2 equivalents) in oneportion. The reaction turned from colorless to a red colored solutionupon the addition of the Dess Martin reagent. The reaction was allowedto stir at room temperature for 1 hour before sodium thiosulfate (10%,25 mL) and EtOAc (25 mL) were added to quench the reaction. The quenchedreaction was allowed to stir for 1 hour and in this time the red coloredsolution faded to a colorless solution. The aqueous layer was extractedtwice with EtOAc. The combined organic phases were washed with sodiumbicarbonate, brine, and dried with sodium sulfate. The dried solutionwas filtered and concentrated to give a crude product which wassubjected to column chromatography (12 gram Isco, 5 to 75% EtOAc inhexanes) to yield 83 mg (84%) ofN-(1-cyclobutyl-6-formyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamidethat was used directly in the next reaction.

Step B

The freshly prepared aldehyde(N-(1-cyclobutyl-6-formyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide,37 mg, 0.118 mmol) from the above experimental was dissolved indichloromethane (2 mL) and TEA-3HF (58 mg, 3 equivalents) was addedbefore the portionwise addition of XtalFluor-E (81 mg, 3 equivalents) atroom temperature. LC/MS analysis at 3 hours of reaction time showed slowprogression of the reaction. Therefore, two more equivalents of eachreagent were added to the reaction. LC/MS analysis 4 hours later showedslow and clean conversion to the desired product. The reaction wasallowed to stir overnight and then quenched by the addition of saturatedsodium bicarbonate (20 mL) and diluted with dichloromethane (20 mL). Thequenched reaction was allowed to stir for 15 minutes and then extractedwith dichloromethane (3×) and the combined organics were washed withbrine, dried with sodium sulfate, filtered and concentrated to give acrude material. The crude material was subjected to silica gelchromatography (12 gram Isco, 0-25% EtOAc in hexanes, product is higherin R_(f) than the corresponding aldehyde) to give the titled compound(7.5 mg, 19% yield) as a white solid. MS (ESI) m/z 336.4 (MH⁺),retention time=3.37 min (Method B). The intermediate aldehyde was alsorecovered from the chromatography (16 mg, 43%). (See: Couturier, M. etal, J. Org. Chem. 2010, 75, 3401-3411).

Example 1. Preparation ofN-(1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide

SolidN-(6-bromo-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide(75 mg) was dissolved in chloroform (9 mL) and methanol (3 mL) beforethe addition of palladium on carbon (10%, 30 mg). The mixture wasallowed to stir for 2 minutes before the dropwise addition oftriethylsilane (0.9 mL). The reaction was allowed to stir for 30 minutesand then passed though filter paper. The filtrate was concentrated andsubjected to silica gel chromatography (12 gram Isco column, 0 to 70%EtOAc in hexanes) to give the desired product that contained animpurity. The material was further purified by subjecting it to anothersilica gel column (4 gram silica gel Isco, 0-10% MeOH indichloromethane) to give a pure sample of the titled compound (22 mg,31% yield) as a foamy white solid. MS (ESI) m/z 286.4 (MH⁺), retentiontime=2.71 min (Method B). (see Mandal, P K, McMurray, J S, J. Org. Chem.2007, 72, 6599-6601).

Example 22. Preparation of(R)—N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-2-(methyl(2,2,2-trifluoroethyl)amino)propanamide

Step A: Preparation of (R)-tert-butyl(1-((6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

2-Amino-3-cyclobutyl-3H-imidazo[4,5-b]pyridine-5-carbonitrile (100 mg,0.47 mmol) and (R)-2-((tert-butoxycarbonyl)(methyl)amino)propanoic acid(115 mg, 0.57 mmol) were used following Method 7 to provide the desiredproduct (112 mg, 59%).

Step B: Preparation of(R)—N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-2-(methylamino)propanamidehydrochloride

To a solution of (R)-tert-butyl(1-((6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate(112 mg, 0.30 mmol) from Step A in MeOH (4 mL) was added concentratedaqueous hydrochloric acid (3 mL) at room temperature. The mixture wasstirred for one hour and then concentrated in vacuo. The residue wasconcentrated twice from methanol to provide the desired product (98 mg,99%).

Step C: Preparation of(R)—N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-2-(methyl(2,2,2-trifluoroethyl)amino)propanamide

DIEA (130 μL, 0.76 mmol) was added to a room temperature solution of(R)—N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-2-(methylamino)propanamidehydrochloride from Step B in dimethyformamide (2 mL). The mixture wasstirred for several minutes and then was treated with2,2,2-trifluoroethyl trifluoromethanesulfonate (55 μL, 0.38 mmol). Themixture was stirred for eight hours with additional DIEA (130 μL, 0.76mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (55 μL, 0.38mmol) being added at two hour intervals over the duration of thereaction. The mixture was concentrated in vacuo and purified by silicagel chromatography (10-50% EtOAc/hexanes) to provide the title compound(24 mg, 21%). MS (ESI) m/z 380.4 (MH⁺).

Example 24. Preparation ofN-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3-(dimethylamino)-4,4,4-trifluorobutanamide

To tert-butyl(4-((6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)amino)-1,1,1-trifluoro-4-oxobutan-2-yl)carbamate(23 mg, 0.051 mmol, prepared according to the procedure of Method 7using 3-((tert-butoxycarbonyl)amino)-4,4,4-trifluorobutanoic acid) inCH₂Cl₂ (1 mL) was added CF₃CO₂H (1 mL) and the mixture was stirred atroom temperature for 1 hour. Solvents were removed by rotaryevaporation, the residue was dissolved in EtOAc, washed sequentiallywith saturated NaHCO₃, brine, then dried (Na₂SO₄), filtered andconcentrated to give3-amino-N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluorobutanamide(18 mg, 0.051 mmol) as a colorless oil. This material was dissolved in20:1 CH₃OH/HOAc (0.5 mL) followed by Et₃N (9 μL, 0.10 mmol) andformaldehyde solution (37% in H₂O, 12 μL, 0.23 mmol). NaCNBH₃ (18 mg,0.51 mmol) was added and the mixture was stirred at room temperature for4 hours. Solvent was concentrated by rotary evaporation, the residue wasdistributed between saturated aqueous NaHCO₃ and EtOAc and the layerswere separated. The aqueous layer was extracted with EtOAc, the extractswere combined, dried (Na₂SO₄), filtered and concentrated. Purificationwas run on a 4 g silica gel column eluting with 0-50% EtOAc/hexanes togive the title compound (11.8 mg, 61%). MS (ESI) m/z 380.4 (MH⁺).

Section 4. Exemplary Syntheses for Examples in Table 1 InvolvingPreparation of Branched Chiral 1H-benzo[d]imidazol-2-yl amides Example18. Preparation of(2S,3R)—N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3-hydroxy-2-methyl-3-phenylbutanamide

Step A: Preparation of (2S,3R)-3-hydroxy-2-methyl-3-phenylbutanoic acid

A solution of (R)-4-benzyl-3-propionyloxazolidin-2-one (1.0 g, 4.3 mmol)in tetrahydrofuran (10 mL) was added dropwise to a −78° C. solution ofLiN(TMS)₂ (1.0 M in tetrahydrofuran, 4.5 mL, 4.5 mmol) intetrahydrofuran (14 mL). The mixture was stirred for 30 minutes at −78°C. and then acetophenone (0.53 mL, 4.5 mmol) was added over 10 minutes.The −78° C. mixture was stirred for two hours and then quenched via theaddition of saturated aqueous NH₄Cl. The mixture was warmed to roomtemperature and extracted twice with EtOAc. The combined organics weredried over anhydrous Na₂SO₄ and concentrated. The residue was purifiedby silica gel chromatography (0-20% EtOAc/hexanes) to provide partiallyseparated mixtures of the oxazolidinone starting material and fourpossible diastereomers (R_(f)=0.57 in 1:4 EtOAc/hexanes, 0.56 g, 37%,(2S,3S) containing fraction; R_(f)=0.50 in 1:4 EtOAc/hexanes, 0.26 g,17%, (2S,3R) containing fraction). Stereochemical assignment for theobserved two major diastereomers were made via extrapolation from datareported in Bartroli, et al; J. Org. Chem., 1995, 60, 3000.

Step B: Preparation of(R)-4-benzyl-3-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-methyl-3-phenylbutanoyl)oxazolidin-2-one

tert-Butyldimethylsilyl trifluoromethanesulfonate (200 μL, 0.88 mmol)was added dropwise to a solution of the diastereomeric mixturecontaining (2S,3R)-3-hydroxy-2-methyl-3-phenylbutanoic acid isolatedfrom Step A (0.26 g, 0.74 mmol) and Et₃N (200 μL, 1.5 mmol) in CH₂Cl₂ (5mL). The solution was stirred at room temperature for one hour and thenpartitioned between EtOAc and saturated aqueous NaHCO₃. The phases wereseparated and the organics were washed with saturated aqueous NaCl. Theorganics were dried over anhydrous Na₂SO₄ and concentrated. The residuewas purified twice by silica gel chromatography (0-20% EtOAc/hexanes andthen 0-50% CH₂Cl₂/hexanes) to provide the expected product (0.11 g,32%).

Step C: Preparation of(2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-methyl-3-phenylbutanoic acid

Lithium hydroxide (29 mg, 1.2 mmol) and 30% aqueous hydrogen peroxide(0.12 mL, 1.2 mmol) were added to a 0° C. mixture of(R)-4-benzyl-3-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-methyl-3-phenylbutanoyl)oxazolidin-2-onefrom Step B (110 mg, 0.24 mmol) in 1:1 tetrahydrofuran/H₂O (3 mL). Themixture was stirred at 0° C. to room temperature overnight. The mixturewas adjusted to pH 2 via the addition of 1 M aqueous HCl and thentreated with solid NaCl until the solids failed to dissolve. The mixturewas then partitioned between saturated aqueous NaCl and EtOAc. Thephases were separated and the aqueous layer was extracted again withEtOAc. The organics were combined, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by silica gel chromatography(0-50% CH₂Cl₂/hexanes) to provide the expected product (10 mg, 24%).

Step D: Preparation of(2S,3R)-3-((tert-butyldimethylsilyl)oxy)-N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-2-methyl-3-phenylbutanamide

A mixture of2-amino-3-cyclobutyl-3H-imidazo[4,5-b]pyridine-5-carbonitrile (7.0 mg,0.032 mmol),(2S,3R)-3-((tert-butyldimethylsilyloxy)-2-methyl-3-phenylbutanoic acidfrom Step C (10 mg, 0.032 mmol), HOBt (7.0 mg, 0.049 mmol), EDC (8.0 mg,0.049 mmol) and diisopropylethylamine (17 μL, 0.097 mmol) indimethyformamide (2 mL) were stirred at 50° C. for 3 days. The mixturewas cooled to room temperature and partitioned between water and EtOAc.The aqueous phase was extracted twice more with EtOAc. The combinedorganics were washed with saturated aqueous NaCl, dried over anhydrousNa₂SO₄ and concentrated. This crude material was used as is in the nextstep.

Step E: Preparation of(2S,3R)—N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3-hydroxy-2-methyl-3-phenylbutanamide

TBAF (1.0 M tetrahydrofuran, 160 μL, 0.16 mmol) was added to a solutionof the crude product from Step D above in tetrahydrofuran (0.32 mL). Themixture was stirred at 50° C. overnight, cooled to room temperature andconcentrated. The residue was purified by reverse phase chromatography(10% CH₃CN/H₂O to CH₃CN) to afford the title compound (1.7 mg, 14% overtwo steps). MS (ESI) m/z 389.2 (MH⁺).

Example 29. Preparation of(S)—N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide

Step A: Preparation of(S)-4-benzyl-3-((S)-3-hydroxy-3-phenylbutanoyl)oxazolidin-2-one

Lithium bis(trimethylsilyl)amide (1.0 M tetrahydrofuran, 9.2 mL, 9.2mmol) was added over 15 minutes to a −78° C. suspension of(S)-3-acetyl-4-benzyloxazolidin-2-one (2.0 g, 9.2 mmol) intetrahydrofuran (9 mL). The mixture was stirred at −78° C. for twohours. A solution of acetophenone (485 μL, 4.2 mmol) in tetrahydrofuran(3 mL) was added over 35 minutes. The mixture was stirred at −78° C. forone hour and then quenched via the addition of aqueous 0.5 M HCl. Themixture was warmed to room temperature and then extracted with CH₂Cl₂.The layers were separated and the aqueous phase was extracted twice morewith CH₂Cl₂. The combined organics were dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by silica gel chromatography(0-30% EtOAc/hexanes) to provide the desired compound in a partiallypurified fashion (1.6 g) that was used as is. The stereochemistry wasassigned as reported in Theurer, et al; Tetrahedron, 2010, 66, 3814.

Step B: Preparation of(S)-4-benzyl-3-((S)-3-((tert-butyldimethylsilyl)oxy)-3-phenylbutanoyl)oxazolidin-2-one

tert-Butyldimethylsilyl trifluoromethanesulfonate (1.3 mL, 5.7 mmol) wasadded dropwise to a room temperature solution of the residue prepared asdescribed in Step A and Et₃N (1.1 mL, 7.5 mmol) in CH₂Cl₂ (24 mL). Themixture was stirred at room temperature overnight and then partitionedbetween EtOAc and saturated aqueous NaHCO₃. The phases were separatedand the organics were washed with saturated aqueous NaCl. The twoaqueous phases were then sequentially extracted twice with EtOAc. Thecombined organics were dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified twice by silica gel chromatography (0-30%EtOAc/hexanes and then 0-50% CH₂Cl₂/hexanes) to provide the expectedproduct (0.57 g, 30% over two steps).

Step C: Preparation of(S)-3-((tert-butyldimethylsilyl)oxy)-3-phenylbutanoic acid

Lithium hydroxide (150 mg, 6.3 mmol) and 30% aqueous hydrogen peroxide(0.64 mL, 6.3 mmol) were added to a 0° C. mixture of(S)-4-benzyl-3-((S)-3-((tert-butyldimethylsilyl)oxy)-3-phenylbutanoyl)oxazolidin-2-onefrom Step B (570 mg, 1.3 mmol) in 1:1 tetrahydrofuran/H₂O (13 mL). Themixture was stirred at 0° C. to room temperature over 80 minutes. Themixture was adjusted to pH 2 via the addition of 1 M aqueous HCl andthen treated with solid NaCl until the solids failed to dissolve. Themixture was then partitioned between saturated aqueous NaCl and EtOAc.The phases were separated and the aqueous layer was extracted again withEtOAc. The organics were combined, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by silica gel chromatography(0-60% EtOAc/hexanes) to provide the expected product (0.21 g, 57%).

The title compound was then prepared using the procedures described inStep D and Step E of Example 18. MS (ESI) m/z 375 (MH⁺).

Example 30. Preparation of(R)—N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide

The same procedure was used to prepare the title compound as was usedfor Example 29 with the exception of starting with(R)-3-acetyl-4-benzyloxazolidin-2-one instead of the (S)-enantiomer. MS(ESI) m/z 375 (MH⁺).

Example 20. Preparation of(S)—N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3-hydroxy-3-(pyridin-2-yl)butanamide

The same procedure was used to prepare the title compound as was usedfor Example 29 with the exception of starting with(R)-3-acetyl-4-benzyloxazolidin-2-one instead of the (S)-enantiomer, andusing 2-acetopyridine in place of acetophenone. MS (ESI) m/z 376 (MH⁺).Stereochemical assignment based on Peters R, et al., J. Org. Chem. 2006,71, 7583-7595.

Example 21. Preparation of(S)—N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3-hydroxy-3-(pyridine-3-yl)butanamide

The same procedure was used to prepare the title compound as was usedfor Example 29 with the exception of starting with(R)-3-acetyl-4-benzyloxazolidin-2-one instead of the (S)-enantiomer andusing 3-acetopyridine in place of acetophenone.

Example 23. Preparation of(S)—N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-2,3,3-trimethylbutanamide

Step A: Preparation of(S)-4-benzyl-3-(3,3-dimethylbutanoyl)oxazolidin-2-one

A 1.0 L round bottom flask was charged with a stir bar, tetrahydrofuran(200 mL, anhydrous) and (S)-4-benzyloxazolidin-2-one (10.0 g, 56.4mmol). The flask was placed in a −78° C. bath for 15 minutes prior tothe addition of n-BuLi (2.5 M in hexanes, 25.0 mL, 1.1 equivalents)dropwise under a nitrogen atmosphere. The reaction was allowed to stirfor 1 hour prior to the addition of 3,3-dimethylbutanoyl chloride (11.7mL, 1.5 equivalents). The reaction was allowed to stir at −78° C. andthen the cooling bath was removed and the flask was allowed to slowlywarm to room temperature and stir overnight. The reaction was quenchedby the addition of saturated aqueous sodium bicarbonate (200 mL) and thebulk of the tetrahydrofuran was removed by rotary evaporation. Theremaining residue was dissolved in ethyl acetate (300 mL) and washedsequentially with saturated aqueous sodium bicarbonate (twice),saturated aqueous sodium carbonate (twice), and brine and then driedover sodium sulfate. The dried solution was filtered and concentrated togive 20 g of crude product. The material was recrystallized from warmethyl acetate (approximately 30 mL) and warm hexanes (approximately 70mL) to give the first crop of the desired product (9.0 g. 58% yield) aswhite crystals. An additional second crop (3.8 g, 25% yield) wasobtained from the mother liquor. ¹H NMR (CDCl₃): δ 7.36-7.22 (m, 5H),4.73-4.67 (m, 1H), 4.18-4.12 (m, 2H), 3.34 (dd, J=13.28, 3.32 Hz, 1H),2.99 (d, J=14.9 Hz, 1H), 2.86 (d, J=14.9 Hz, 1H), 2.71 (dd, J=13.24,10.00 Hz, 1H), 1.09 (br s, 9H).

Step B: Preparation of(S)-4-benzyl-3-((S)-2,3,3-trimethylbutanoyl)oxazolidin-2-one

Freshly recrystallized(S)-4-benzyl-3-(3,3-dimethylbutanoyl)oxazolidin-2-one (8.75 g, 31.77mmol) was azeotroped with dichloromethane (2×, 30 mL) and then placedunder high vacuum for 10 minutes prior to being dissolved intetrahydrofuran (40 mL). In a 1.0 L round bottom flask fitted with aballoon of nitrogen and a stir bar was placed NaHMDS (1.0 M intetrahydrofuran, 35 mL, 1.1 equivalents) and the flask was placed in a−78° C. bath. After being chilled for 15 minutes, the 40 mLtetrahydrofuran solution of(S)-4-benzyl-3-(3,3-dimethylbutanoyl)oxazolidin-2-one was added dropwiseto the NaHMDS at −78° C. The formation of the sodium enolate was allowedto form over 1 hour at −78° C. and then methyl iodide (6 mL, 3equivalents) was added via syringe. The reaction was allowed to stir andslowly warm to room temperature overnight. The reaction was quenched bythe addition of saturated aqueous sodium bicarbonate (150 mL) and thebulk of the tetrahydrofuran was removed by rotary evaporation. Theresidue was transferred to a separatory funnel using ethyl acetate andsaturated aqueous sodium bicarbonate. The layers were separated and theorganic layer was washed with 10% aqueous sodium thiosulfate (150 mL) toremove the pale yellow color. The combined organic layers were backextracted with ethyl acetate (2×). The combined organics were washedwith brine, dried with sodium sulfate, filtered and concentrated to givea white solid (8.61 g, 94% yield). ¹H NMR analysis indicated completeconversion of starting material to the methylated products and anapproximately 15:1 diastereomeric ratio of products in favor of thedesired (S)-4-benzyl-3-((S)-2,3,3 trimethylbutanoyl)oxazolidin-2-onediastereomer A. An attempt to enrich the diastereomeric ratio byrecrystallization from warm hexanes failed to improve the diastereomericratio. Therefore, the initial solid product was divided into threeportions and each one was subjected to column chromatography (Isco, 120g silica gel, 0-10% EtOAc in hexanes). The higher running R_(f)fractions of the UV peak were cut off from the later running fractionsto give a product of improved diastereomeric ratio (1.83 g,approximately 70:1 d.r.) as a white solid. The chromatography wasrepeated on the original product to give two samples of improveddiastereomeric ratio (2.28 g, >20:1 d.r and 4.59 g, 30:1 d.r.) in favorof (S)-4-benzyl-3-((S)-2,3,3-trimethylbutanoyl)oxazolidin-2-onediastereomer. Major diastereomer A ¹H NMR (CDCl₃): δ 7.33-7.23 (m, 5H),4.73-4.67 (m, 1H), 4.17-4.13 (m, 2H), 3.90 (q, J=7.00 Hz, 1H), 3.28 (dd,J=13.32, 3.20 Hz, 1H), 2.77 (dd, J=13.32, 9.72 Hz, 1H), 1.20 (d, J=7.00Hz, 3H), 1.02 (bs, 9H). The latter running R_(f) fraction were combinedto give the desired product in a diminished diastereomeric ratio (360mg, 3:1 d.r.) contaminated with the undesired(S)-4-benzyl-3-((R)-2,3,3-trimethylbutanoyl)oxazolidin-2-one minordiastereomer B (Reference: Evans, D A; Ennis, M D; Mathre, D J J. Am.Chem. Soc. 1982, 104, 1737-1739).

Step C: Preparation of (S)-2,3,3-trimethylbutanoic acid

Solid (S)-4-benzyl-3-((S)-2,3,3-trimethylbutanoyl)oxazolidin-2-one (2.24g, 7.73 mmol, diastereomer A from Step B above, approx. 30:1 d.r) wasdissolved in tetrahydrofuran (50 mL) and water (10 mL) and the flask wasallowed to chill in a 0° C. for 10 minutes prior to the addition oflithium hydroxide (326 mg, 13.6 mmol, 2 equivalents) in one portion.After a few minutes, hydrogen peroxide (30%, 6 mL) was added viasyringe. After approximately 30 min, an additional portion oftetrahydrofuran (60 mL) and water (10 mL) were added to the flask. Thereaction was allowed to stir at 0° C. for 1 hour and then allowed towarm to room temperature and stirred for 24 hours. The flask wasrechilled to 0° C. and then quenched by the addition of sodium sulfite(19 g in 125 mL of water) and saturated aqueous sodium bicarbonate (75mL). The quenched reaction was allowed to stir for 1.5 hours and thenthe bulk of the tetrahydrofuran was removed by rotary evaporation. Themixture was transferred to a separatory funnel using dichloromethane andsaturated aqueous sodium bicarbonate. The aqueous layer was extractedwith dichloromethane (3×50 mL) to remove the bulk of the chiralauxiliary. The aqueous layer was carefully acidified with HCl (1 M,until pH=2) and then extracted with dichloromethane (4×50 mL). Thecombined organics were washed with brine and dried with sodium sulfate.The dried solution was filtered and carefully evaporated to give thedesired carboxylic acid as an oil (925 mg, >100% yield, dichloromethaneimpurity). The (S)-2,3,3-trimethylbutanoic acid was diluted up to avolume of 9 mL with dichloromethane to make a stock solution that wasused directly in the amide coupling reaction. ¹H NMR (CDCl₃): δ 12.02(br s, 1H), 2.29 (q, J=7.08 Hz, 1H), 1.13 (d, J=7.08 Hz, 3H), 0.99 (brs, 9H). (Reference: Evans, D A, Britton, T C, Ellman, J A, TetrahedronLeft. 1987, 28(49), 6141-6144).

Step D: Preparation of(S)—N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-2,3,3-trimethylbutanamide

The dichloromethane stock solution of (S)-2,3,3-trimethylbutanoic acidfrom Step C above was transferred to a tared flask and carefullyevaporated. This acid was dissolved in dimethyformamide and the standardamide coupling Method 7 was followed to give the desired product.

Example 13. Preparation of(S)—N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3-hydroxy-2,3-dimethylbutanamide

Step A. Preparation of(R)-4-benzyl-3-((S)-3-hydroxy-2,3-dimethylbutanoyl)oxazolidin-2-one

Commercially available (R)-4-benzyl-3-propionyloxazolidin-2-one (3.0 g,12.85 mmol, 1.0 equivalents) was dissolved in dichloromethane (40 mL)and chilled to 0° C. for 10 minutes prior to the addition of TiCl₄ (1.0M in dichloromethane, 14.15 mL, 1.1 equivalents) via syringe under anatmosphere of nitrogen. After 5 minutes, diisopropylethylamine (2.5 mL,1.1 equivalents) was added dropwise via syringe. The reaction wasallowed to stir at 0° C. for 1 hour and a dark-red titanium enolateformed. At this time, acetone (1.4 mL, 1.5 equivalents, dried overanhydrous potassium carbonate for 24 hours) was added via syringe. Thereaction was allowed to stir at 0° C. for 15 minutes and then slowlyallowed to warm to room temperature overnight. The reaction was quenchedby the addition of aqueous ammonium chloride (1 M, 100 mL) and extractedwith dichloromethane (three times). The combined organics were washedwith brine, dried with sodium sulfate, filtered and concentrated to give4.0 g of a crude oil. The crude oil was subjected to columnchromatography (Isco, 120 g silica gel, 0-25% EtOAc in hexanes) to givethe desired product (3.0 g, 80% yield) as a white solid. NMR analysisindicated a single diastereomer of the purified product. R_(f)=0.75 in20% EtOAc in hexanes. ¹H NMR (CDCl₃): δ 7.32-7.23 (m, 5H), 4.72-4.66 (m,1H), 4.20-4.13 (m, 2H), 3.95 (q, J=7.00 Hz, 1H), 3.38-3.34 (m, 2H), 2.75(dd, J=13.36, 9.88 Hz, 1H), 1.35 (s, 3H), 1.24-1.23 (m, 6H). (Reference:Evans, D A, Urpi, F, Somers, T C. Clark, J S, Bilodeau, M T, J. Am.Chem. Soc. 1990, 112, 8215-8216).

Step B: Preparation of(R)-4-benzyl-3-((S)-3-((tert-butyldimethylsilyl)oxy)-2,3-dimethylbutanoyl)oxazolidin-2-one

The solid tertiary alcohol (1000 mg, 3.43 mmol, 1.0 equivalents) fromthe above procedure,(R)-4-benzyl-3-((S)-3-hydroxy-2,3-dimethylbutanoyl)oxazolidin-2-one, wasdissolved in dichloromethane (10 mL) and diisopropylethylamine (0.9 mL,1.5 equivalents) was added via syringe. The flask was chilled for 10minutes in a 0° C. bath prior to the drop wise addition oftert-butyldimethylsilyl triflate (0.9 mL, 1.1 equivalents) via syringe.The reaction was allowed to stir overnight and then quenched by theaddition of saturated aqueous sodium bicarbonate (50 mL). The aqueouslayer was extracted twice with dichloromethane. The combined organicswere washed with brine, dried with sodium sulfate, filtered andconcentrated to give a crude oil. The crude material was subjected tosilica gel column chromatography (Isco, 24 g silica gel, 0-20% EtOAc inhexanes) to give the desired TBS ether (1.23 g, 95%) as a white solid.R_(f)=0.75 in 20% EtOAc in hexanes. ¹H NMR (CDCl₃): δ 7.24-7.12 (m, 5H),4.57-4.51 (m, 1H), 4.10-3.93 (m, 3H), 3.33 (dd, J=13.08, 3.16 Hz, 1H),2.47 (dd, J=13.00, 10.88 Hz, 1H), 1.25 (s, 3H), 1.24 (s, 3H), 1.07 (d,J=7.00 Hz, 3H), 0.76 (bs, 9H), 0.00 (d, J=5.72 Hz, 6H).

Step C: Preparation of(S)-3-((tert-butyldimethylsilyl)oxy)-2,3-dimethylbutanoic acid

Solid(R)-4-benzyl-3-((S)-3-((tert-butyldimethylsilyl)oxy)-2,3-dimethylbutanoyl)oxazolidin-2-one(3.8 g, 9.7 mmol, >30:1 d.r) was dissolved in tetrahydrofuran (50 mL)and water (10 mL) and the flask was allowed to chill in a 0° C. for 5minutes prior to the addition of lithium hydroxide (450 mg, 18.7 mmol, 2equivalents) in one portion. After a few minutes, hydrogen peroxide(30%, 12 mL) was added via syringe. The reaction was allowed to stir at0° C. for 1 hour and then allowed to warm to room temperature andstirred for 24 hours. The flask was rechilled to 0° C. and then quenchedby the addition of sodium sulfite (12 g in 100 mL of water). Thequenched reaction was allowed to stir for 1.5 hours and then the bulk ofthe tetrahydrofuran was removed by rotary evaporation. The mixture wastransferred to a separatory funnel using dichloromethane and saturatedaqueous sodium bicarbonate. The aqueous layer was extracted withdichloromethane (2×50 mL). This initial dichloromethane extract wasfound to contain both the chiral auxiliary and the desired TBS etheracid. The combined organics were washed with brine and dried with sodiumsulfate, filtered and concentrated to give the crude product as oil (3.1g). The crude material was subjected to silica gel column chromatography(Isco, 40 g, 0-25% EtOAc in hexanes, ELSD detection) to give the desiredproduct as oil (1.2 g, 52% yield). R_(f)=0.50 in 20% EtOAc in hexanes,purple to anisaldehyde stain and is not UV active. ¹H NMR (CDCl₃): δ10.4-9.80 (br s, 1H), 2.32 (q, J=7.16 Hz, 1H), 1.19 (s, 3H), 1.14 (s,3H), 1.03 (d, J=7.16 Hz, 3H), 0.72 (s, 9H), 0.00 (s, 6H).

Step D: Preparation(S)-3-((tert-butyldimethylsilyl)oxy)-N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-2,3-dimethylbutanamide

Method 7 was used to provide the desired amide product (38 mg, 65%yield), isolated via column chromatography. The isolated material wascontaminated with the activated ester of the corresponding carboxylicacid coupling partner. The material was taken forward to the next stepwithout any further purification.

Step E: Preparation of(S)—N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3-hydroxy-2,3-dimethylbutanamideVia Deprotection of TBDMS Ether

Crude(S)-3-((tert-butyldimethylsilyl)oxy)-N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-2,3-dimethylbutanamidefrom Step D above (38 mg) was dissolved in MeOH (4 mL) and HCl (3 M indiethyl ether, 2 mL) was added to the reaction via syringe. The reactionwas allowed to stir at room temperature for 30 minutes when LC/MSanalysis indicated a slow and clean deprotection of the TBS ether. Theflask was placed in a 50° C. sand bath and allowed to stir capped for 20hours. The flask was allowed to cool and then quenched by the carefuladdition of saturated aqueous sodium bicarbonate (30 mL) and ethylacetate (30 mL). The aqueous layer was extracted twice with ethylacetate. The combined organics were washed with brine, dried with sodiumsulfate, filtered and concentrated to give a crude oil. The crudematerial was subjected to column chromatography (Isco, 12 g silica gel,5-75% EtOAc in hexanes) to give the desired product (18 mg, 64% yield).MS (ESI) m/z 327.2 (MH⁺).

Example 12. Preparation ofN-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3-methoxy-3-methylbutanamide

Step A. Preparation of 3-methoxy-3-methylbutanoic acid

To a solution of 3-methoxy-3-methylbutan-1-ol (0.6 g, 5 mmol) inacetonitrile (20 mL) was added N-methyl morpholine N-oxide monohydrate(6.8 g, 50 mmol, 10 equivalents) and the mixture was allowed to stir atroom temperature. After 5 min, tetrapropylammonium perruthenate (175 mg,0.5 mmol, 0.1 equivalents) was added in one portion and the reaction wasallowed to stir for 3 h before the bulk of the solvent was carefullyremoved on a rotary evaporator (caution, the product is volatile). Theresidue was purified by column chromatography (50-100% EtOAc/hexanes).The hexanes and EtOAc were removed by both rotary evaporator and a shortperiod of time to high vacuum. The product is volatile and must not beleft under vacuum for more than 30 sec. The resulting purified acid wasdiluted with dimethyformamide (7 mL) to make an approximately 0.2 Msolution that was used for amide coupling reaction as is. R_(f)=0.4 to0.8 streak in 100% EtOAc, not UV active, stains purple to anisaldehyde.M−1=131.2. ¹H NMR (CDCl₃): δ 12.0-9.0 (bs, 1H), 3.30 (s, 3H), 2.57 (s,2H), 1.32 (s, 6H). (Reference: Schmidt, A-K C, Stark, B W, Org. Lett.2011, 13, 4164-4167).

Step B. Preparation ofN-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3-methoxy-3-methylbutanamide

The title compound was prepared from 3-methoxy-3-methylbutanoic acid and4-amino-3-(cyclobutylamino) benzonitrile according to Method 7. MS (ESI)m/z 327 (MH⁺).

Example 103. Preparation of(S)—N-(6-chloro-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3-(4-fluorophenyl)-3-hydroxybutanamide

Step A: Preparation of(S)-4-benzyl-3-((S)-3-(4-fluorophenyl)-3-hydroxybutanoyl)oxazolidin-2-one

Lithium bis(trimethylsilyl)amide (1.0 M tetrahydrofuran, 6.6 mL, 6.6mmol) was added over 15 minutes to a −78° C. suspension of(S)-3-acetyl-4-benzyloxazolidin-2-one (1.5 g, 6.6 mmol) intetrahydrofuran (18 mL). The mixture was stirred at −78° C. for twohours. Acetophenone (330 μL, 3.2 mmol) was added dropwise over 5minutes. The mixture was stirred at −78° C. for one hour and thenquenched via the addition of aqueous 0.5 M HCl. The mixture was warmedto room temperature and then extracted with CH₂Cl₂. The layers wereseparated and the aqueous phase was extracted twice more with CH₂Cl₂.The combined organics were dried over anhydrous Na₂SO₄ and concentrated.The residue was purified by silica gel chromatography (0-30%EtOAc/hexanes) to provide the desired (0.80 g).

Step B: Preparation of (S)-3-(4-fluorophenyl)-3-hydroxybutanoic acid

Lithium hydroxide (210 mg, 9.0 mmol) was added to a 0° C. mixture of(S)-4-benzyl-3-((S)-3-(4-fluorophenyl)-3-hydroxybutanoyl)oxazolidin-2-one(0.80 g, 2.2 mmol) and 50% aqueous hydrogen peroxide (0.51 mL, 9.0 mmol)in 1:1 tetrahydrofuran/H₂O (9 mL). The mixture was stirred at 0° C. for15 minutes, then at room temperature for three hours. The mixture wasadjusted to pH 7 via the addition of 1 M aqueous HCl and then wasdiluted with EtOAc. The layers were separated, the aqueous phase wasadjusted to pH 2 via the addition of 1 M aqueous HCl and then treatedwith solid NaCl until the solids failed to dissolve. The mixture wasthen partitioned between saturated aqueous NaCl and EtOAc. The phaseswere separated and the aqueous layer was extracted again with EtOAc. Theorganics were combined, dried over anhydrous Na₂SO₄ and concentrated toprovide the expected product (0.35 g, 79%).

The title compound was then prepared using the procedures described inStep D of Example 18, substituting(S)-3-(4-fluorophenyl)-3-hydroxybutanoic acid for(2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-methyl-3-phenylbutanoic acidand 6-chloro-1-cyclobutyl-1H-benzo[d]imidazol-2-amine for2-amino-1-cyclobutyl-1H-benzo[d]imidazole-6-carbonitrile. MS (ESI) m/z402 (MH⁺).

Preparation of 2-(1-hydroxycyclopentyl)acetic acid

Step A. Preparation of ethyl 2-(1-hydroxycyclopentyl)acetate

Chlorotrimethylsilane (181 μL, 1.4 mmol) was added to a suspension ofzinc powder (1.2 g, 19 mmol) in Et₂O (30 mL). The mixture was stirred atroom temperature for 15 minutes and then refluxed for 15 minutes. Theheat source was removed and ethyl bromoacetate (1.8 mL, 14 mmol) wasadded dropwise to the warm mixture. The mixture was then refluxed forone hour and then stirred at room temperature for one hour.Cyclopentanone (1.0 g, 12 mmol) was then added dropwise. The resultingmixture was stirred for one hour and then poured into ice coldconcentrated aqueous ammonia (80 mL). The layers were separated and theaqueous phase was extracted with Et₂O (3×40 mL). The combined organicswere dried (K₂CO₃) and concentrated to yield 1.7 g of a colorless oil.This material was used as is in the next step.

Step B. Preparation of 2-(1-hydroxycyclopentyl)acetic acid

Lithium hydroxide (1.4 g, 58 mmol) was added to a room temperaturesolution of the crude ester prepared as described in the previous step(1.0 g, 5.8 mmol) in 1:1 EtOH:water (29 mL). After 2 hours, the reactionwas partitioned between water (100 mL) and MTBE (100 mL). The aqueouslayer was isolated and the pH was adjusted to pH=2 with 1.0 N aqueousHCl. The aqueous mixture was extracted three times with EtOAc. Thecombined organics were dried (Na₂SO₄) and concentrated to afford thedesired product (500 mg, 60%). (ESI) m/z 143.2 (M-H).

The following carboxylic acids were prepared using an analogousprocedure to that described for preparation of2-(1-hydroxycyclopentyl)acetic acid with appropriate starting materials.

-   3,3-dicyclopropyl-3-hydroxypropanoic acid-   3-cyclopentyl-3-hydroxybutanoic acid-   3-cyclobutyl-3-hydroxybutanoic acid

Preparation of 3-hydroxy-2,2-dimethyl-3-phenylpropanoic acid

The preparation of 3-hydroxy-2,2-dimethyl-3-phenylpropanoic acid isdetailed in J. Org. Chem., 2012, 77 (11), 4885-4901.

Section 5. General Analytical Methods.

LCMS was conducted on an Agilent 1100 MSD instrument equipped with anAscentis Express C18, 10 cm×4.6 mm×2.7 mm column, using the followingmethods:

HPLC Method A

Solvent A: 0.1% formic acid in water

Solvent B: Acetonitrile

Flow rate: 1.4 mL/min

Method:

0-6.0 min gradient from B=10% to B=95%

6.0-8.0 min, hold B=95%

8.0-8.2 min, gradient from B=95% to B=10%

8.2-10.0 min, hold B=10%

HPLC Method B:

Solvent A: 0.1% formic acid in water

Solvent B: Acetonitrile

Flow rate: 1.4 mL/min

Method:

0-3.0 min gradient from B=10% to B=95%

3.0-4.0 min, hold B=95%

4.0-4.2 min, gradient from B=95% to B=10%

4.2-6.0 min, hold B=10%

Table 1 shows the structures of the various Examples prepared by thesegeneral methods, and indicates the general coupling method used,together with a summary of the LCMS analytical data.

TABLE 1 List of Examples, Synthetic Routes and Analytical Data HPLCCoupling Retention Method/ HPLC time LCMS Ex. Structure Name final stepMethod (min) m/z 1

N-(1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide  7 B2.7 286 2 C₁₉H₂₁N₃O 3,3-dimethyl-N-(1-phenyl-1H- benzo[d]imidazol-2-yl)butanamide  9 B 2.8 308 3

3-cyclopentyl-N-(1-isopropyl- 6-methoxy-1H- benzo[d]imidazol-2-yl)propanamide 12 A 5.5 330 4

(S)-N-(1-isopropyl-6- methoxy-1H- benzo[d]imidazol-2-yl)-2,3-dimethylbutanamide  7 B 2.7 304 5

N-(6-cyano-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide  7 B 3.5 311 6

(S)-N-(6-cyano-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-2,3-dimethylbutanamide  7 B 3.5 311 7

(S)-N-(6-cyano-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-2,3-dimethylbutanamide  7 A 4.9 311 8

N-(6-cyano-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-3-hydroxy-3-methylbutanamide  7 B 2.7 313 9

N-(6-cyano-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-3,3-difluorocyclobutane-1- carboxamide  7 B 3.5 331 10

(1S,2R,4R)-N-(6-cyano-1- cyclobutyl-1H- benzo[d]imidazol-2-yl)bicyclo[2.2.1]heptane-2- carboxamide  7 B 3.6 335 11

(S)-N-(6-cyano-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-2,2-dimethylcyclopropane-1- carboxamide  7 B 3.3 309 12

N-(6-cyano-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-3- methoxy-3-methylbutanamide  7 B 3.0 327 13

(S)-N-(6-cyano-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-3- hydroxy-2,3-dimethylbutanamide  7 B 2.9 327 14

(R)-N-(6-cyano-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-2,3-dimethylbutanamide  7 B 3.5 311 15

(1S,2S)-N-(6-cyano-1- cyclobutyl-1H- benzo[d]imidazol-2-yl)-2-(2-hydroxypropan-2- yl)cyclopropane-1- carboxamide  7 B 2.8 339 16

(S)-N-(6-cyano-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-3,3,3-trifluoro-2-hydroxy-2- methylpropanamide  7 B 3.8 353 17

N-(6-cyano-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide  7 B 3.4 375 18

(2S,3R)-N-(6-cyano-1- cyclobutyl-1H- benzo[d]imidazol-2-yl)-3-hydroxy-2-methyl-3- phenylbutanamide Ex 18 B 3.5 389 19

(2S,3S)-N-(6-cyano-1- cyclobutyl-1H- benzo[d]imidazol-2-yl)-3-hydroxy-2-methyl-3- phenylbutanamide Ex 19 B 3.8 389 20

(S)-N-(6-cyano-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-3-hydroxy-3-(pyridin-2- yl)butanamide  7 (no base) A 2.9 376 21

(S)-N-(6-cyano-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-3-hydroxy-3-(pyridin-3- yl)butanamide  7 B 2.3 376 22

(R)-N-(6-cyano-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-2- (methyl(2,2,2-trifluoroethyl)amino) propanamide  7 B 3.6 380 23

(S)-N-(6-cyano-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-2,3,3-trimethylbutanamide  7 A 5.3 325 24

N-(6-cyano-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-3-(dimethylamino)-4,4,4- trifluorobutanamide  7 B 3.4 380 25

(R)-N-(6-cyano-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-3- hydroxy-3-phenylpropanamide  7 B 3.1 361 26

(S)-N-(6-cyano-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-3- hydroxy-3-phenylpropanamide  7 B 3.1 361 27

(S)-N-(6-cyano-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-2-(1-hydroxycyclobutyl) propanamide  7 B 3.1 339 28

N-(6-cyano-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-3- cyclopropyl-3-hydroxybutanamide  7 B 3.1 339 29

(S)-N-(6-cyano-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide 10 B 3.4 375 30

(R)-N-(6-cyano-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide 10 B 3.4 375 31

N-(6-cyano-1-(4- fluorophenyl)-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide  7 B 3.5 351 32

(S)-N-(6-cyano-1-(4- fluorophenyl)-1H- benzo[d]imidazol-2-yl)-2,3-dimethylbutanamide  7 B 3.5 351 33

(S)-N-(6-cyano-1-(4- fluorophenyl)-1H- benzo[d]imidazol-2-yl)-2,2-dimethylcyclopropane-1- carboxamide  7 B 3.4 349 34

N-(1-cyclobutyl-6- (trifluoromethyl)-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide  7 B 3.9 354 35

N-(1-cyclobutyl-6- (trifluoromethyl)-1H- benzo[d]imidazol-2-yl)-3-hydroxy-3-methylbutanamide  7 B 3.2 356 36

(S)-N-(1-cyclobutyl-6- (trifluoromethyl)-1H- benzo[d]imidazol-2-yl)-2,3-dimethylbutanamide  7 B 4.0 354 37

(S)-N-(1-cyclobutyl-6- (trifluoromethyl)-1H- benzo[d]imidazol-2-yl)-2,2-dimethylcyclopropane-1- carboxamide  7 B 3.8 352 38

N-(1-cyclobutyl-6- (trifluoromethyl)-1H- benzo[d]imidazol-2-yl)-3,3-difluorocyclobutane-1- carboxamide  7 B 4.1 374 39

N-(1-cyclobutyl-6- (trifluoromethyl)-1H- benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3- (trifluoromethyl)butanamide  7 B 4.6 448 40

(R)-N-(1-cyclobutyl-6- (trifluoromethyl)-1H- benzo[d]imidazol-2-yl)-2,3-dimethylbutanamide  7 B 4.0 354 41

(1S,2S)-N-(1-cyclobutyl-6- (trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-2-(2- hydroxypropan-2- yl)cyclopropane-1-carboxamide  7 B 3.2 382 42

(S)-N-(1-cyclobutyl-6- (trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3,3- trifluoro-2-hydroxy-2- methylpropanamide  B 4.3 396 43

(R)-N-(1-cyclobutyl-6- (trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3,3- trifluoro-2-hydroxy-2- methylpropanamide 7 B 4.3 369 44

N-(1-cyclobutyl-6- (trifluoromethyl)-1H- benzo[d]imidazol-2-yl)-2-(1-hydroxycyclobutyl)acetamide  7 B 3.4 368 45

(S)-2,2-dimethyl-N-(1-(3- methylisoxazol-5-yl)-6- (trifluoromethyl)-1H-benzo[d]imidazol-2- yl)cyclopropane-1- carboxamide 11 B 3.9 379 46

3,3-dimethyl-N-(1-(3- methylisoxazol-5-yl)-6- (trifluoromethyl)-1H-benzo[d]imidazol-2- yl)butanamide  9 B 3.9 381 47

(S)-2,3-dimethyl-N-(1-(3- methylisoxazol-5-yl)-6- (trifluoromethyl)-1H-benzo[d]imidazol-2- yl)butanamide 11 B 3.9 381 48

(S)-2,3,3-trimethyl-N-(1-(3- methylisoxazol-5-yl)-6-(trifluoromethyl)-1H- benzo[d]imidazol-2- yl)butanamide 11 B 4.0 395 49

(S)-N-(6-cyano-1-(3- methylisoxazol-5-yl)-1H-benzo[d]imidazol-2-yl)-2,3,3- trimethylbutanamide 11 B 3.6 352 50

ethyl 1-cyclobutyl-2-(3,3- dimethylbutanamido)-1H- benzo[d]imidazole-6-carboxylate  7 B 3.7 358 51

N-(1-cyclobutyl-6- (hydroxymethyl)-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide  7 A 2.4 316 52

(S)-N-(1-cyclobutyl-6- (hydroxymethyl)-1H- benzo[d]imidazol-2-yl)-2,3-dimethylbutanamide  7 B 2.4 316 53

N-(1-cyclobutyl-6-(2- hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide  7 B 2.5 344 54

(S)-N-(1-cyclobutyl-6-(2- hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2,3- dimethylbutanamide  7 B 2.5 344 55

N-(1-cyclobutyl-6-(1- hydroxyethyl)-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide  7 B 2.4 330 56

(2S)-N-(1-cyclobutyl-6-(1- hydroxyethyl)-1H- benzo[d]imidazol-2-yl)-2,3-dimethylbutanamide  7 B 2.4 330 57

N-(1-cyclobutyl-6-(1- hydroxypropyl)-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide  7 B 2.6 344 58

(S)-N-(6-chloro-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-2,2-dimethylcyclopropane-1- carboxamide  7 B 3.4 318 59

(S)-N-(6-chloro-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-2,3-dimethylbutanamide  7 B 3.7 320 60

N-(6-chloro-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide  7 B 3.6 320 61

N-(6-chloro-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-2-(3,3-difluorocyclobutyl) acetamide  7 B 3.8 355 62

N-(6-chloro-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-2-(1-hydroxycyclobutyl)acetamide  7 B 3.0 334 63

N-(6-bromo-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide  7 B 3.8 366 64

N-(1-cyclobutyl-6-isopropyl- 1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide  7 B 3.2 328 65

(S)-N-(1-cyclobutyl-6- isopropyl-1H- benzo[d]imidazol-2-yl)-2,3-dimethylbutanamide  7 B 3.4 328 66

N-(1-cyclobutyl-6- (difluoromethyl)-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide  7 B 3.4 336 67

methyl 1-cyclobutyl-2-(3,3- dimethylbutanamido)-1H- benzo[d]imidazole-7-carboxylate  7 B 3.2 344 68

N-(1-cyclobutyl-7- (hydroxymethyl)-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide  7 B 2.7 316 69

N-(6-cyano-1-(3- methylisoxazol-5-yl)-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide  9 B 3.4 338 70

(R)-N-(6-cyano-1-(4- fluorophenyl)-1H- benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide 7 with (R)- 3-((tert- butyldimethyl-silyl)oxy)-3- phenylbutanoic acid as acid, then procedure analogous toex. 18, step E B 3.4 415 71

(S)-N-(6-cyano-1-(4- fluorophenyl)-1H- benzo[d]imidazol-2-yl)-2,3,3-trimethylbutanamide  7 B 3.6 365 72

N-(6-cyano-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-3-hydroxy-2,2-dimethyl-3- phenylpropanamide  7 B 3.8 389 73

(S)-N-(6-cyano-1-(5- fluoropyridin-2-yl)-1H- benzo[d]imidazol-2-yl)-2,3-dimethylbutanamide  7 B 3.4 352 74

N-(6-cyano-1-(5- fluoropyridin-2-yl)-1H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide  9 B 3.4 352 75

(S)-N-(6-cyano-1-(5- fluoropyridin-2-yl)-1H-benzo[d]imidazol-2-yl)-2,3,3- trimethylbutanamide  7 B 3.6 366 76

(R)-N-(6-cyano-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-2,3,3-trimethylbutanamide  7 A 5.3 325 77

N-(6-cyano-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-2,3,3-trimethylbutanamide  7 A 5.3 325 78

N-(6-cyano-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-3- cyclobutyl-3-hydroxybutanamide  7 B 3.3 353 79

(S)-N-(6-cyano-1-(5- fluoropyridin-2-yl)-1H- benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide  7 B 3.3 416 80

N-(6-cyano-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-3- cyclopentyl-3-hydroxybutanamide  7 B 3.5 367 81

N-(6-cyano-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-2-(1-hydroxycyclopentyl)acetamide  7 B 3.0 339 82

N-(1-cyclobutyl-7-(2- hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 7, followed by methoddescribed for Ex. 53 with Ex. 67 as starting material B 3.5 344 83

(S)-N-(1-cyclobutyl-6-(2- hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2- (6,6-dimethyltetrahydro-2H-pyran-2-yl)acetamide 7, followed by method described for Ex. 53 B 2.6400 84

(S)-N-(1-cyclobutyl-6-(2- hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3- hydroxy-3-phenylbutanamide 7, followed bymethod described for Ex. 53 B 2.7 408 85

N-(1-cyclobutyl-6-(2- hydroxypropan-2-yl)-1H- benzo[d]imidazol-2-yl)-3-hydroxy-3-methylbutanamide 7, followed by method described for Ex. 53 B2.1 346 86

(S)-N-(1-cyclobutyl-6-(2- hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2,3,3- trimethylbutanamide 7, followed by methoddescribed for Ex. 53 B 2.6 358 87

N-(1-cyclobutyl-6-(2- hydroxypropan-2-yl)-1H- benzo[d]imidazol-2-yl)spiro[3.3]heptane-2- carboxamide 7, followed by method described forEx. 53 B 2.7 368 88

(S)-N-(1-cyclobutyl-6- (trifluoromethyl)-1H- benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide  7 B 3.9 418 89

(R)-N-(1-cyclobutyl-6-(2- hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2,2- dimethylcyclopropane-1- carboxamide 7,followed by method described for Ex. 53 B 2.4 342 90

N-(1-cyclobutyl-6-(2- hydroxypropan-2-yl)-1H- benzo[d]imidazol-2-yl)pivalamide 7, followed by method described for Ex. 53 B 2.9 330 91

(R)-N-(1-(tert-butyl)-6-cyano- 1H-benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide  7 B 3.6 369 92

(S)-N-(1-(tert-butyl)-6-cyano- 1H-benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide  7 B 3.6 369 93

(S)-N-(1-(tert-butyl)-6-cyano- 1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3-hydroxy-3- methylbutanamide  7 B 3.5 377 94

(R)-N-(1-(tert-butyl)-6-cyano- 1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-3-hydroxy-3- methylbutanamide  7 B 3.5 377 95

(S)-N-(6-cyano-1-(1- methylcyclobutyl)-1H- benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide  7 B 3.6 389 96

(R)-N-(6-cyano-1-(1- methylcyclobutyl)-1H- benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide  7 B 3.6 389 97

N-(1-cyclobutyl-6-(2- hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3- dicyclopropyl-3- hydroxypropanamide 7,followed by method described for Ex. 53 B 2.6 398 98

N-(1-cyclobutyl-6- (trifluoromethyl)-1H- benzo[d]imidazol-2-yl)-3,3-dicyclopropyl-3- hydroxypropanamide  7 B 4.0 408 99

(S)-N-(6-chloro-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide  7 B 3.8 384 100

(R)-N-(6-chloro-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide  7 B 3.7 384 101

N-(1-cyclobutyl-6-(2- hydroxypropan-2-yl)-1H- benzo[d]imidazol-2-yl)spiro[2. 3]hexane-1- carboxamide 7, followed by method described forEx. 53 B 2.5 354 102

N-(1-cyclobutyl-6-(2- hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3- difluorocyclopentane-1- carboxamide 7,followed by method described for Ex. 53 B 2.7 378 103

(S)-N-(6-chloro-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-3-(4-fluorophenyl)-3- hydroxybutanamide  7 B 3.9 402 104

N-(1-(4-fluorophenyl)-6-(2- hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 7, followed by methoddescribed for Ex. 53 B 2.7 384 105

N-(1-cyclobutyl-6-(2- hydroxypropan-2-yl)-1H- benzo[d]imidazol-2-yl)spiro[2.2]pentane-1- carboxamide 7, followed by method described forEx. 53 B 2.4 340 106

N-(1-cyclobutyl-6-(3- hydroxypentan-3-yl)-1H- benzo[d]imidazol-2-yl)spiro[2.2]pentane-1- carboxamide 7, followed by method described forEx. 53 with EtMgBr B 2.6 368 107

(S)-N-(6-chloro-1-(4- fluorophenyl)-1H- benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide  7 B 3.7 424 108

(R)-N-(6-chloro-1-(4- fluorophenyl)-1H- benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide  7 B 3.7 424 109

N-(1-(4-fluorophenyl)-6-(2- hydroxypropan-2-yl)-1H- benzo[d]imidazol-2-yl)spiro[2.2]pentane-1- carboxamide 7, followed by method described forEx. 53 B 2.5 380 110

ethyl 2-(1-cyclobutyl-2-(3,3- dimethylbutanamido)-7-fluoro-1H-benzo[d]imidazol- 6-yl)acetate  7 A 5.4 390 111

ethyl (S)-2-(1-cyclobutyl-2- (2,2-dimethylcyclopropane-1-carboxamido)-7-fluoro-1H- benzo[d]imidazol-6-yl)acetate  7 B 3.6 388 112

ethyl 2-(2-(3,3- dimethylbutanamido)-7- fluoro-1-(4-fluorophenyl)-1H-benzo[d]imidazol-6- yl)acetate  7 B 3.7 430 113

(S)-N-(1-cyclobutyl-7-fluoro- 6-(2-hydroxy-2- methylpropyl)-1H-benzo[d]imidazol-2-yl)-2,2- dimethylcyclopropane-1- carboxamide  7 B 3.1374 114

N-(1-cyclobutyl-7-fluoro-6-(2- hydroxy-2-methylpropyl)-1H-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 7, followed by methoddescribed for Ex. 53 B 3.2 376 115

(S)-N-(7-fluoro-1-(4- fluorophenyl)-6-(2-hydroxy-2- methylpropyl)-1H-benzo[d]imidazol-2-yl)-2,2- dimethylcyclopropane-1- carboxamide 7,followed by method described for Ex. 53 B 3.1 414 116

N-(7-fluoro-1-(4- fluorophenyl)-6-(2-hydroxy-2- methylpropyl)-1H-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 7, followed by methoddescribed for Ex. 53 B 3.2 416 117

2-(1-cyclobutyl-2-(3,3- dimethylbutanamido)-7-fluoro-1H-benzo[d]imidazol- 6-yl)acetic acid  7 B 2.9 362 118

N-(1-cyclobutyl-6-(2- (dimethylamino)-2-oxoethyl)- 7-fluoro-1H-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide  7 B 2.9 389 119

(S)-N-(1-(tert-butyl)-6-cyano- 5-methyl-1H - benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide  7 B 3.7 391 120

(R)-N-(1-(tert-butyl)-6-cyano- 5-methyl-1H- benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide  7 B 3.7 391 121

(S)-N-(1-(tert-butyl)-6-cyano- 5-methyl-1H- benzo[d]imidazol-2-yl)-3-(4-fluorophenyl)-3- hydroxybutanamide  7 B 3.8 409 122

(S)-N-(1-(tert-butyl)-6-cyano- 5-methyl-1H- benzo[d]imidazol-2-yl)-3-(2-fluorophenyl)-3- hydroxybutanamide  7 B 3.9 409 123

(S)-N-(6-cyano-1-cyclobutyl- 5-methyl-1H- benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide  7 B 3.5 389 124

(R)-N-(6-cyano-1-cyclobutyl- 5-methyl-1H- benzo[d]imidazol-2-yl)-3-hydroxy-3-phenylbutanamide  7 B 3.5 389 125

(S)-N-(6-cyano-1-cyclobutyl- 5-methyl-1H- benzo[d]imidazol-2-yl)-3-(4-fluorophenyl)-3- hydroxybutanamide  7 B 3.6 407 126

(S)-N-(6-cyano-1-cyclobutyl- 5-methyl-1H- benzo[d]imidazol-2-yl)-3-(2-fluorophenyl)-3- hydroxybutanamide  7 B 3.7 407 127

N-(1-(tert-butyl)-6-cyano-5- methyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide  7 B 3.9 327 128

N-(1-(tert-butyl)-6-cyano-5- methyl-1H-benzo[d]imidazol-2-yl)-3-hydroxy-3- methylbutanamide  7 B 2.8 329 129

N-(1-(tert-butyl)-6-cyano-5- methyl-1H-benzo[d]imidazol-2-yl)-3,3-difluorocyclobutane- 1-carboxamide  7 B 3.9 347 130

N-(6-cyano-1-cyclobutyl-5- methyl-1H-benzo[d]imidazol-2-yl)-3-hydroxy-3- methylbutanamide  7 B 2.8 327 131

4,4,4-trifluoro-N-(1-(4- fluorophenyl)-6-(2- hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3- hydroxy-3- (trifluoromethyl)butanamide 7,followed by method described for Ex. 53 B 3.8 494 132

(R)-N-(1-cyclobutyl-7-fluoro- 5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-4,4,4- trifluoro-3-hydroxy-3- methylbutanamide  7B 4.1 428 133

N-(1-cyclobutyl-7-fluoro-5- (trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3- hydroxy-3-methylbutanamide  7 B 3.5 374 134

(S)-N-(1-(tert-butyl)-6-cyano- 5-methyl-1H-benzo[d]imidazol-2-yl)-4,4,4- trifluoro-3-hydroxy-3- methylbutanamide  7B 3.8 383 135

(R)-N-(1-(tert-butyl)-6-cyano- 5-methyl-1H-benzo[d]imidazol-2-yl)-4,4,4- trifluoro-3-hydroxy-3- methylbutanamide  7B 3.8 383 136

N-(1-(3,5-difluorophenyl)-6- (trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3- hydroxy-3-methylbutanamide  7 B 3.4 414 137

3-hydroxy-3-methyl-N-(1-(4- (trifluoromethoxy)phenyl)-6-(trifluoromethyl)-1H- benzo[d]imidazol-2- yl)butanamide  7 B 3.5 462 138

(S)-N-(6-cyano-1-(1- methylcyclobutyl)-1H- benzo[d]imidazol-2-yl)-3-(4-fluorophenyl)-3- hydroxybutanamide  7 B 3.7 407 139

(S)-3-(2-chlorophenyl)-N-(6- cyano-1-(1- methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3- hydroxybutanamide  7 B 4.0 423 140

(S)-3-(4-chlorophenyl)-N-(6- cyano-1-(1- methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)-3- hydroxybutanamide  7 A 5.7 423 141

N-(1-(3,5-difluorophenyl)-6- (trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-2-(1- hydroxycyclobutyl)acetamide  7 B 3.6 426142

2-(1-hydroxycyclobutyl)-N-(1- (4-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)-1H- benzo[d]imidazol-2- yl)acetamide  7 B 3.8 474143

N-(1-(3,4-difluorophenyl)-6- (trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3- hydroxy-3-methylbutanamide  7 B 3.4 414 144

N-(1-(3-fluoro-4- (trifluoromethoxy)phenyl)-6- (trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-3- hydroxy-3-methylbutanamide  7 B 3.8 480 145

N-(1-(3-fluoro-4- (trifluoromethoxy)phenyl)-6- (trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-2-(1- hydroxycyclobutyl)acetamide  7 B 3.9 492Biological Assay MethodsKv7.2/7.3 Activation Assay

The ability of compounds to potentiate K-currents in Kv7.2/7.3containing HEK cells was assessed using planar patch-clamp on the QPatchautomated screening platform.

Cell Line: The hKv7.2/7.3 cell line was obtained from Chantest(Cleveland, Ohio 44128) cat. #CT6147. These HEK cells will express theKv7.2/7.3 ion channels when induced.

Cell Culture: Cells were maintained in a media containing DMEM/F12;50/50 (GIBCO cat. #11330), 10% Fetal Bovine Serum (FBS) (GIBCO cat.#26140), 100 units/mL Penicillin-Streptomycin (GIBCO cat. #15140), 0.005mg/mL Blasticidin (INVIVOGEN cat. #ant-bl-1), 0.5 mg/mL Geneticin (GIBCOcat. #10131), 0.1 mg/mL Zeocin (GIBCO cat. #R25001). Cells used in theelectrophysiology assay were maintained in a media without Blasticidin,Geneticin and Zeocin for 2 days and channel expression was induced byadding tetracycline (BIOLINE cat. #BIO-87030) at a final concentrationof 1 mg/mL. Cells were grown in T-175 flask to ˜75% confluency. Currentswere recorded 24 hours after channel induction.

Compound Plates: Test compounds were prepared by performing serialdilutions on a Biomek NX^(P) (BECKMAN COULTER). Final dilutions weremade in external recording solution with a final DMSO concentration of0.1% DMSO. For single concentration screens each plate had 10 μMretigabine as a positive control and 0.1% DMSO as a negative control.

Electrophysiology: On the day of the experiment cells were washed withHank's Balanced Salt Solution (HBBS) (GIBCO cat. #14175) and harvestedwith Tryple (GIBCO cat. #12604). Cells were then centrifuged at 2000 rpmfor 5 minutes and resuspended in CHO-S-SFM (GIBCO cat. #12052) at ˜3×10⁶cells/mL. Cells were stirred for 30 minutes before experiments werestarted. External recording solution contained (in mM): NaCl (145), KCl(4), CaCl₂ (2), MgCl₂ (1), HEPES (10) and Glucose (10); pH was adjustedto 7.4 with NaOH and the osmolarity was adjusted to 300-305 mOsM withsucrose if necessary. Internal solution contained (in mM): KCl (125), KF(10), EGTA (5), Na₂ATP (5), MgCl₂ (3.2), HEPES (5); pH was adjusted to7.2 with KOH and the osmolarity was adjusted to 298-302 mOsM withsucrose.

Potassium channel activity was measured on the QPatch HTX (SophionBioscience) using QPlates with 48-wells/plate. Each cell was taken as anindependent experiment and only one compound was tested per well.Potassium channel activity was elicited by holding at −80 mV andstepping to −30 mV for 2 s followed by a 100 ms pulse to −120 mV.

Single concentration screen: Baseline conditions were obtained byrecording 5 sweeps in the external solution only, this was repeated forthree applications of the external solution. The effect of testcompounds on elicited current was then assessed by recording 5 sweeps inthe presence of a 3 μM compound solution. The steady-state current atthe end of the 2 s pulse to −30 mV was measured to determine the foldincrease from baseline.

TABLE 2 Kv7.2/7.3 Single Concentration Screen Results. Example Kv7.2/7.3Activity* 1 + 2 + 3 +++ 4 +/− 5 +++ 6 + 7 + 8 + 9 + 10 + 11 ++ 12 +/− 13+/− 14 +/− 15 +/− 16 +/− 17 ++ 18 + 19 + 20 + 21 +/− 22 +/− 23 ++ 24 +25 +/− 26 +/− 27 +/− 28 +/− 29 + 30 + 31 + 32 + 33 + 34 ++ 35 + 36 +37 + 38 +/− 39 + 40 + 41 +/− 42 +/− 43 +/− 44 + 45 + 46 + 47 + 48 +++49 + 50 +/− 51 + 52 +/− 53 + 54 ++ 55 + 56 ++ 57 + 58 + 59 + 60 + 61 +62 + 63 ++ 64 ++ 65 + 66 ++ 67 +/− 68 + 69 + 70 +/− 71 + 72 +/− 73 +/−74 + 75 ++ 76 + 77 + 78 + 79 + 80 + 81 + 82 +/− 83 ++ 84 + 85 +/− 86 +++87 ++ 88 + 89 ++ 90 +/− 91 +/− 92 + 93 + 94 +/− 95 ++ 96 ++ 97 +/− 98 +99 + 100 + 101 + 102 +/− 103 + 104 + (@ 1 μM) 105 + 106 +/− 107 + 108+/− 109 + 110 + 111 + 112 ++ 113 + 114 + 115 + 116 + 117 +/− 118 + 119+/− 120 + 121 + 122 ++ 123 +/− 124 +/− 125 +/− 126 ++ 127 + 128 +/− 129+/− 130 +/− 131 +/− 132 +/− 133 + 134 +/− 135 +/− 136 + 137 + 138 +139 + 140 +/− 141 + 142 ++ 143 ++ 144 + 145 ++ *Increase in current fromKv7.2/Kv7.3 co-expressing HEK cells, measured at compound concentrationof 3 μM, as a range from <1.2-fold increase over baseline (−) upto >6-fold increase over baseline (+++).

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe specification and attached claims are approximations that may varydepending upon the desired properties sought to be obtained. At the veryleast, and not as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical parameter shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the invention (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.,“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of any claim. Nolanguage in the specification should be construed as indicating anynon-claimed element essential to the practice of the invention.

Groupings of alternative elements or embodiments disclosed herein arenot to be construed as limitations. Each group member may be referred toand claimed individually or in any combination with other members of thegroup or other elements found herein. It is anticipated that one or moremembers of a group may be included in, or deleted from, a group forreasons of convenience and/or patentability. When any such inclusion ordeletion occurs, the specification is deemed to contain the group asmodified thus fulfilling the written description of all Markush groupsused in the appended claims.

Certain embodiments are described herein, including the best mode knownto the inventors for carrying out the invention. Of course, variationson these described embodiments will become apparent to those of ordinaryskill in the art upon reading the foregoing description. The inventorexpects skilled artisans to employ such variations as appropriate, andthe inventors intend for the invention to be practiced otherwise thanspecifically described herein. Accordingly, the claims include allmodifications and equivalents of the subject matter recited in theclaims as permitted by applicable law. Moreover, any combination of theabove-described elements in all possible variations thereof iscontemplated unless otherwise indicated herein or otherwise clearlycontradicted by context.

In closing, it is to be understood that the embodiments disclosed hereinare illustrative of the principles of the claims. Other modificationsthat may be employed are within the scope of the claims. Thus, by way ofexample, but not of limitation, alternative embodiments may be utilizedin accordance with the teachings herein. Accordingly, the claims are notlimited to embodiments precisely as shown and described.

The invention claimed is:
 1. A compound represented by a formula:

wherein: D is optionally substituted cyclobutyl, optionally substitutedphenyl, optionally substituted isoxazolyl, optionally substitutedpyridinyl, isopropyl, or t-butyl; A is C₁₋₈ alkyl; X is optionallysubstituted phenyl; Y is OH; R¹ is H, Cl, Br, CN, OCH₃, CF₃, —CO₂CH₂CH₃,C₁₋₄ alkyl, or C₁₋₄ hydroxyalkyl; and R² is H, F, —CH₂OH, —CO₂Me, or—C(CH₃)₂OH; R³ is H, F, Cl, Br, I, or a substituent having a molecularweight of 15 Da to 200 Da and consisting of 2 to 5 chemical elements,wherein the chemical elements are independently C, H, O, N, S, F, Cl, orBr; and R⁴ is H, —CH₃, or —CF₃; or a pharmaceutically acceptable saltthereof.
 2. The compound of claim 1, wherein: R² is H, F, —CH₂OH,—CO₂Me, or —C(CH₃)₂OH; R³ is H; and R⁴ is H, —CH₃, or —CF₃.
 3. Apharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable excipient.
 4. A pharmaceutical compositioncomprising a compound of claim 2 and a pharmaceutically acceptableexcipient.
 5. The compound of claim 1, wherein D is optionallysubstituted cyclobutyl.
 6. The compound of claim 1, wherein D isoptionally substituted phenyl.
 7. The compound of claim 1, wherein D isoptionally substituted isoxazolyl.
 8. The compound of claim 1, wherein Dis optionally substituted pyridinyl.
 9. The compound of claim 1, whereinD is isopropyl or t-butyl.
 10. The compound of claim 1, wherein R¹ is H.11. The compound of claim 1, wherein R¹ is Cl or Br.
 12. The compound ofclaim 1, wherein R¹ is CN, OCH₃, or CF₃.
 13. The compound of claim 1,wherein R¹ is —CO₂CH₂CH₃, C₁₋₄ alkyl, or C₁₋₄ hydroxyalkyl.
 14. Thecompound of claim 1, wherein R² is H or F.
 15. The compound of claim 1,wherein R² is —CH₂OH, —CO₂Me, or —C(CH₃)₂OH.
 16. The compound of claim1, wherein R³ is H.
 17. The compound of claim 1, wherein R³ is F, Cl,Br, or I.
 18. The compound of claim 1, wherein R³ is a substituenthaving a molecular weight of 15 Da to 200 Da and consisting of 2 to 5chemical elements, wherein the chemical elements are independently C, H,O, N, S, F, Cl, or Br.
 19. The compound of claim 1, wherein R⁴ is H. 20.The compound of claim 1, wherein R⁴ is —CH₃, or —CF₃.